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El-Shemi AG, Alqurashi A, Abdulrahman JA, Alzahrani HD, Almwalad KS, Felfilan HH, Alomiri WS, Aloufi JA, Madkhali GH, Maqliyah SA, Alshahrani JB, Kamal HT, Daghistani SH, Refaat B, Minshawi F. IL-10-Directed Cancer Immunotherapy: Preclinical Advances, Clinical Insights, and Future Perspectives. Cancers (Basel) 2025; 17:1012. [PMID: 40149345 PMCID: PMC11940594 DOI: 10.3390/cancers17061012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2025] [Revised: 03/12/2025] [Accepted: 03/14/2025] [Indexed: 03/29/2025] Open
Abstract
Interleukin-10 (IL-10) is a dimeric cytokine encoded by the IL-10 gene on chromosome 1 [...].
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Affiliation(s)
- Adel G. El-Shemi
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, Makkah 21955, Saudi Arabia; (A.G.E.-S.); (J.A.A.); (H.D.A.); (K.S.A.); (H.H.F.); (W.S.A.); (J.A.A.); (G.H.M.); (S.A.M.); (J.B.A.); (H.T.K.); (S.H.D.); (B.R.)
- Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt
| | | | - Jihan Abdullah Abdulrahman
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, Makkah 21955, Saudi Arabia; (A.G.E.-S.); (J.A.A.); (H.D.A.); (K.S.A.); (H.H.F.); (W.S.A.); (J.A.A.); (G.H.M.); (S.A.M.); (J.B.A.); (H.T.K.); (S.H.D.); (B.R.)
| | - Hanin Dhaifallah Alzahrani
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, Makkah 21955, Saudi Arabia; (A.G.E.-S.); (J.A.A.); (H.D.A.); (K.S.A.); (H.H.F.); (W.S.A.); (J.A.A.); (G.H.M.); (S.A.M.); (J.B.A.); (H.T.K.); (S.H.D.); (B.R.)
| | - Khawlah Saad Almwalad
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, Makkah 21955, Saudi Arabia; (A.G.E.-S.); (J.A.A.); (H.D.A.); (K.S.A.); (H.H.F.); (W.S.A.); (J.A.A.); (G.H.M.); (S.A.M.); (J.B.A.); (H.T.K.); (S.H.D.); (B.R.)
| | - Hadeel Hisham Felfilan
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, Makkah 21955, Saudi Arabia; (A.G.E.-S.); (J.A.A.); (H.D.A.); (K.S.A.); (H.H.F.); (W.S.A.); (J.A.A.); (G.H.M.); (S.A.M.); (J.B.A.); (H.T.K.); (S.H.D.); (B.R.)
| | - Wahaj Saud Alomiri
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, Makkah 21955, Saudi Arabia; (A.G.E.-S.); (J.A.A.); (H.D.A.); (K.S.A.); (H.H.F.); (W.S.A.); (J.A.A.); (G.H.M.); (S.A.M.); (J.B.A.); (H.T.K.); (S.H.D.); (B.R.)
| | - Jana Ahmed Aloufi
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, Makkah 21955, Saudi Arabia; (A.G.E.-S.); (J.A.A.); (H.D.A.); (K.S.A.); (H.H.F.); (W.S.A.); (J.A.A.); (G.H.M.); (S.A.M.); (J.B.A.); (H.T.K.); (S.H.D.); (B.R.)
| | - Ghadeer Hassn Madkhali
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, Makkah 21955, Saudi Arabia; (A.G.E.-S.); (J.A.A.); (H.D.A.); (K.S.A.); (H.H.F.); (W.S.A.); (J.A.A.); (G.H.M.); (S.A.M.); (J.B.A.); (H.T.K.); (S.H.D.); (B.R.)
- Department of Hematology, Dr. Sulaiman Al-Habib Medical Diagnostic Laboratory, Olaya District, Riyadh 12234-3785, Saudi Arabia
| | - Sarah Adel Maqliyah
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, Makkah 21955, Saudi Arabia; (A.G.E.-S.); (J.A.A.); (H.D.A.); (K.S.A.); (H.H.F.); (W.S.A.); (J.A.A.); (G.H.M.); (S.A.M.); (J.B.A.); (H.T.K.); (S.H.D.); (B.R.)
- Department of Blood Bank and Laboratory, Saudi German Hospital, Makkah 24242, Saudi Arabia
| | - Jood Bandar Alshahrani
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, Makkah 21955, Saudi Arabia; (A.G.E.-S.); (J.A.A.); (H.D.A.); (K.S.A.); (H.H.F.); (W.S.A.); (J.A.A.); (G.H.M.); (S.A.M.); (J.B.A.); (H.T.K.); (S.H.D.); (B.R.)
| | - Huda Taj Kamal
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, Makkah 21955, Saudi Arabia; (A.G.E.-S.); (J.A.A.); (H.D.A.); (K.S.A.); (H.H.F.); (W.S.A.); (J.A.A.); (G.H.M.); (S.A.M.); (J.B.A.); (H.T.K.); (S.H.D.); (B.R.)
| | - Sawsan Hazim Daghistani
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, Makkah 21955, Saudi Arabia; (A.G.E.-S.); (J.A.A.); (H.D.A.); (K.S.A.); (H.H.F.); (W.S.A.); (J.A.A.); (G.H.M.); (S.A.M.); (J.B.A.); (H.T.K.); (S.H.D.); (B.R.)
| | - Bassem Refaat
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, Makkah 21955, Saudi Arabia; (A.G.E.-S.); (J.A.A.); (H.D.A.); (K.S.A.); (H.H.F.); (W.S.A.); (J.A.A.); (G.H.M.); (S.A.M.); (J.B.A.); (H.T.K.); (S.H.D.); (B.R.)
| | - Faisal Minshawi
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, Makkah 21955, Saudi Arabia; (A.G.E.-S.); (J.A.A.); (H.D.A.); (K.S.A.); (H.H.F.); (W.S.A.); (J.A.A.); (G.H.M.); (S.A.M.); (J.B.A.); (H.T.K.); (S.H.D.); (B.R.)
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Aldrete CA, Call CC, Sant'Anna LE, Vlahos AE, Pei J, Cong Q, Gao XJ. Orthogonalized human protease control of secreted signals. Nat Chem Biol 2025:10.1038/s41589-024-01831-x. [PMID: 39814991 DOI: 10.1038/s41589-024-01831-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 12/18/2024] [Indexed: 01/18/2025]
Abstract
Synthetic circuits that regulate protein secretion in human cells could support cell-based therapies by enabling control over local environments. Although protein-level circuits enable such potential clinical applications, featuring orthogonality and compactness, their non-human origin poses a potential immunogenic risk. In this study, we developed Humanized Drug Induced Regulation of Engineered CyTokines (hDIRECT) as a platform to control cytokine activity exclusively using human-derived proteins. We sourced a specific human protease and its FDA-approved inhibitor. We engineered cytokines (IL-2, IL-6 and IL-10) whose activities can be activated and abrogated by proteolytic cleavage. We used species specificity and re-localization strategies to orthogonalize the cytokines and protease from the human context that they would be deployed in. hDIRECT should enable local cytokine activation to support a variety of cell-based therapies, such as muscle regeneration and cancer immunotherapy. Our work offers a proof of concept for the emerging appreciation of humanization in synthetic biology for human health.
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Affiliation(s)
- Carlos A Aldrete
- Department of Chemical Engineering, Stanford University, Stanford, CA, USA
| | - Connor C Call
- Department of Chemical Engineering, Stanford University, Stanford, CA, USA
| | - Lucas E Sant'Anna
- Department of Bioengineering, Stanford University, Stanford, CA, USA
| | - Alexander E Vlahos
- Department of Chemical Engineering, Stanford University, Stanford, CA, USA
| | - Jimin Pei
- Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Qian Cong
- Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Xiaojing J Gao
- Department of Chemical Engineering, Stanford University, Stanford, CA, USA.
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Li J, Wu Z, Wu Y, Hu X, Yang J, Zhu D, Wu M, Li X, Bentum-Ennin L, Wanglai H. IL-22, a vital cytokine in autoimmune diseases. Clin Exp Immunol 2024; 218:242-263. [PMID: 38651179 PMCID: PMC11557150 DOI: 10.1093/cei/uxae035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 03/05/2024] [Accepted: 04/19/2024] [Indexed: 04/25/2024] Open
Abstract
Interleukin-22 (IL-22) is a vital cytokine that is dysregulated in various autoimmune conditions including rheumatoid arthritis (RA), multiple sclerosis (MS), and Alzheimer's disease (AD). As the starting point for the activation of numerous signaling pathways, IL-22 plays an important role in the initiation and development of autoimmune diseases. Specifically, imbalances in IL-22 signaling can interfere with other signaling pathways, causing cross-regulation of target genes which ultimately leads to the development of immune disorders. This review delineates the various connections between the IL-22 signaling pathway and autoimmune disease, focusing on the latest understanding of the cellular sources of IL-22 and its effects on various cell types. We further explore progress with pharmacological interventions related to targeting IL-22, describing how such therapeutic strategies promise to usher in a new era in the treatment of autoimmune disease.
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Affiliation(s)
- Jiajin Li
- The Second Clinical School of Medicine, Anhui Medical University, Hefei, China
| | - Zhen Wu
- The First Clinical School of Medicine, Anhui Medical University, Hefei, China
| | - Yuxin Wu
- The First Clinical School of Medicine, Anhui Medical University, Hefei, China
| | - XinYu Hu
- The Second Clinical School of Medicine, Anhui Medical University, Hefei, China
| | - Jun Yang
- The Second Clinical School of Medicine, Anhui Medical University, Hefei, China
| | - Dacheng Zhu
- The First Clinical School of Medicine, Anhui Medical University, Hefei, China
| | - Mingyue Wu
- The School of pharmacy, Anhui Medical University, Hefei, China
| | - Xin Li
- The School of pharmacy, Anhui Medical University, Hefei, China
| | | | - Hu Wanglai
- The School of Basic Medical Sciences, Anhui Medical University, Hefei, China
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Aldrete CA, Call CC, Sant'Anna LE, Vlahos AE, Pei J, Cong Q, Gao XJ. Orthogonalized human protease control of secreted signals. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.18.576308. [PMID: 39484520 PMCID: PMC11526856 DOI: 10.1101/2024.01.18.576308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/03/2024]
Abstract
Synthetic circuits that regulate protein secretion in human cells could support cell-based therapies by enabling control over local environments. While protein-level circuits enable such potential clinical applications, featuring orthogonality and compactness, their non-human origin poses a potential immunogenic risk. Here, we developed Humanized Drug Induced Regulation of Engineered CyTokines (hDIRECT) as a platform to control cytokine activity exclusively using human-derived proteins. We sourced a specific human protease and its FDA-approved inhibitor. We engineered cytokines (IL-2, IL-6, and IL-10) whose activities can be activated and abrogated by proteolytic cleavage. We utilized species specificity and re-localization strategies to orthogonalize the cytokines and protease from the human context that they would be deployed in. hDIRECT should enable local cytokine activation to support a variety of cell-based therapies such as muscle regeneration and cancer immunotherapy. Our work offers a proof of concept for the emerging appreciation of humanization in synthetic biology for human health.
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Affiliation(s)
- Carlos A Aldrete
- Department of Chemical Engineering, Stanford University, Stanford CA 94305, USA
| | - Connor C Call
- Department of Chemical Engineering, Stanford University, Stanford CA 94305, USA
| | - Lucas E Sant'Anna
- Department of Bioengineering, Stanford University, Stanford CA 94305, USA
| | - Alexander E Vlahos
- Department of Chemical Engineering, Stanford University, Stanford CA 94305, USA
| | - Jimin Pei
- Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Qian Cong
- Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Xiaojing J Gao
- Department of Chemical Engineering, Stanford University, Stanford CA 94305, USA
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Kuchař M, Sloupenská K, Rašková Kafková L, Groza Y, Škarda J, Kosztyu P, Hlavničková M, Mierzwicka JM, Osička R, Petroková H, Walimbwa SI, Bharadwaj S, Černý J, Raška M, Malý P. Human IL-22 receptor-targeted small protein antagonist suppress murine DSS-induced colitis. Cell Commun Signal 2024; 22:469. [PMID: 39354587 PMCID: PMC11446014 DOI: 10.1186/s12964-024-01846-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 09/22/2024] [Indexed: 10/03/2024] Open
Abstract
BACKGROUND Human interleukin-22 (IL-22) is known as a "dual function" cytokine that acts as a master regulator to maintain homeostasis, structural integrity of the intestinal epithelial barrier, and shielding against bacterial pathogens. On the other hand, the overexpression of IL-22 is associated with hyper-proliferation and recruitment of pathologic effector cells, leading to tissue damage and chronic inflammation in specific diseases including inflammatory bowel disease (IBD). To study a role of IL-22-mediated signaling axis during intestinal inflammation, we generated a set of small protein blockers of IL-22R1 and verified their inhibitory potential on murine model of colitis. METHODS We used directed evolution of proteins to identify binders of human IL-22 receptor alpha (IL-22R1), designated as ABR ligands. This approach combines the assembly of a highly complex combinatorial protein library derived from small albumin-binding domain scaffold and selection of promising protein variants using ribosome display followed by large-scale ELISA screening. The binding affinity and specificity of ABR variants were analyzed on transfected HEK293T cells by flow cytometry and LigandTracer. Inhibitory function was further verified by competition ELISA, HEK-Blue IL-22 reporter cells, and murine dextran sulfate sodium (DSS)-induced colitis. RESULTS We demonstrate that ABR specifically recognizes transgenic IL-22R1 expressed on HEK293T cells and IL-22R1 on TNFα/IFNγ-activated HaCaT cells. Moreover, some ABR binders compete with the IL-22 cytokine and function as IL-22R1 antagonists in HEK-Blue IL22 reporter cells. In a murine model of DSS-induced acute intestinal inflammation, daily intraperitoneal administration of the best IL-22R1 antagonist, ABR167, suppressed the development of clinical and histological markers of colitis including prevention of mucosal inflammation and architecture deterioration. In addition, ABR167 reduces the DSS-induced increase in mRNA transcript levels of inflammatory cytokines such as IL-1β, IL-6, IL-10, and IL-17A. CONCLUSIONS We developed small anti-human IL-22R1 blockers with antagonistic properties that ascertain a substantial role of IL-22-mediated signaling in the development of intestinal inflammation. The developed ABR blockers can be useful as a molecular clue for further IBD drug development.
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Affiliation(s)
- Milan Kuchař
- Laboratory of Ligand Engineering, BIOCEV Research Center, Institute of Biotechnology of the Czech Academy of Sciences, Prumyslova 595, Vestec, 252 50, Czech Republic
| | - Kristýna Sloupenská
- Department of Immunology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hnevotinska 3, Olomouc, 779 00, Czech Republic
| | - Leona Rašková Kafková
- Department of Immunology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hnevotinska 3, Olomouc, 779 00, Czech Republic.
| | - Yaroslava Groza
- Laboratory of Ligand Engineering, BIOCEV Research Center, Institute of Biotechnology of the Czech Academy of Sciences, Prumyslova 595, Vestec, 252 50, Czech Republic
| | - Jozef Škarda
- Department of Pathology, University Hospital Ostrava and Faculty of Medicine, University of Ostrava, Syllabova 19, Ostrava, 708 00, Czech Republic
| | - Petr Kosztyu
- Department of Immunology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hnevotinska 3, Olomouc, 779 00, Czech Republic
| | - Marie Hlavničková
- Laboratory of Ligand Engineering, BIOCEV Research Center, Institute of Biotechnology of the Czech Academy of Sciences, Prumyslova 595, Vestec, 252 50, Czech Republic
| | - Joanna M Mierzwicka
- Laboratory of Ligand Engineering, BIOCEV Research Center, Institute of Biotechnology of the Czech Academy of Sciences, Prumyslova 595, Vestec, 252 50, Czech Republic
| | - Radim Osička
- Laboratory of Molecular Biology of Bacterial Pathogens, Institute of Microbiology of the Czech Academy of Sciences, Videnska 1083, Prague, 14220, Czech Republic
| | - Hana Petroková
- Laboratory of Ligand Engineering, BIOCEV Research Center, Institute of Biotechnology of the Czech Academy of Sciences, Prumyslova 595, Vestec, 252 50, Czech Republic
| | - Stephen I Walimbwa
- Department of Immunology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hnevotinska 3, Olomouc, 779 00, Czech Republic
| | - Shiv Bharadwaj
- Laboratory of Ligand Engineering, BIOCEV Research Center, Institute of Biotechnology of the Czech Academy of Sciences, Prumyslova 595, Vestec, 252 50, Czech Republic
| | - Jiří Černý
- Laboratory of Structural Bioinformatics of Proteins, BIOCEV Research Center, Institute of Biotechnology of the Czech Academy of Sciences, Prumyslova 595, Vestec, 252 50, Czech Republic
| | - Milan Raška
- Department of Immunology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hnevotinska 3, Olomouc, 779 00, Czech Republic
| | - Petr Malý
- Laboratory of Ligand Engineering, BIOCEV Research Center, Institute of Biotechnology of the Czech Academy of Sciences, Prumyslova 595, Vestec, 252 50, Czech Republic.
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Pillar A, Ali MK. IL-22 Binding Protein/IL-22 Axis in Regulating Acute Lung Injury. THE AMERICAN JOURNAL OF PATHOLOGY 2024; 194:335-337. [PMID: 38199431 DOI: 10.1016/j.ajpath.2024.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Accepted: 01/02/2024] [Indexed: 01/12/2024]
Affiliation(s)
- Amber Pillar
- School of Biomedical Sciences and Pharmacy, University of Newcastle and The Immune Health Program, Hunter Medical Research Institute, Newcastle, New South Wales, Australia
| | - Md Khadem Ali
- Pre-Professional Health Academic Program, California State University East Bay, Hayward, California.
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Seth P, Dubey S. IL-22 as a target for therapeutic intervention: Current knowledge on its role in various diseases. Cytokine 2023; 169:156293. [PMID: 37441942 DOI: 10.1016/j.cyto.2023.156293] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 06/12/2023] [Accepted: 07/03/2023] [Indexed: 07/15/2023]
Abstract
IL-22 has emerged as a crucial cytokine mediating protective response against pathogens and tissue regeneration. Dysregulated production of IL-22 has been shown to play a pivotal role in the pathogenesis of various diseases like malignant tumours, viral, cardiovascular, allergic and autoimmune disorders. Interleukin 22 belongs to IFN-IL-10 cytokine family. It is a major proinflammatory cytokine secreted by activated Th1 cells (Th22), though can also be secreted by many other immune cells like group 3 innate lymphocytes, γδ T cells, NK cells, NK T cells, and mucosal associated invariant T cells. Th22 cells exclusively release IL-22 but not IL-17 or IFN-γ (as Th1 cells releases IFN-γ along with IL-22 and Th17 cells releases IL-17 along with IL-22) and also express aryl hydrocarbon receptor as the key transcription factor. Th22 cells also exhibit expression of chemokine receptor CCR6 and skin-homing receptors CCR4 and CCR10 indicating the involvement of this subset in bolstering epithelial barrier immunity and promoting secretion of antimicrobial peptides (AMPs) from intestinal epithelial cells. The function of IL-22 is modulated by IL-22 binding protein (binds to IL-22 and inhibits it binding to its cell surface receptor); which serves as a competitor for IL-22R1 chain of IL-22 receptor. The pathogenic and protective nature of the Th22 cells is modulated both by the site of infected tissue and the type of disease pathology. This review aims to discuss key features of IL-22 biology, comparisons between IL and 22 and IFN-γ and its role as a potential immune therapy target in different maladies.
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Affiliation(s)
- Pranav Seth
- Amity Institute of Virology & Immunology, Amity University Uttar Pradesh, Sector 125, Noida, India
| | - Shweta Dubey
- Amity Institute of Virology & Immunology, Amity University Uttar Pradesh, Sector 125, Noida, India.
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Wang X, Yu S, Liu W, Lv P, Zhao L, Wang Y, Fu C, Meng L, Yang Q, Wang X, Huang Y, Zuo Z, Liu X. Relationship between IL-22 and IL-22BP in diabetic cognitive dysfunction. Acta Diabetol 2023; 60:631-644. [PMID: 36717397 DOI: 10.1007/s00592-022-02024-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Accepted: 12/21/2022] [Indexed: 02/01/2023]
Abstract
BACKGROUND CD4 + T helper (Th)22 cells play a regulatory role in autoimmune diseases such as type 1 diabetes mellitus. The Th22-related cytokine interleukin (IL)-22, the expression of which is increased in diabetes mellitus (DM), can act as a neurotrophic factor to protect neurons from apoptosis. Paradoxically, neuronal apoptosis and learning and memory decline occur in DM. In this study, we investigated the relationship between IL-22 and its receptors IL-22Rα1 and IL-22 binding protein (IL-22BP, a soluble inhibitor of IL-22) in diabetic encephalopathy (DE) and the effects of IL-22 on hippocampal neurons, learning and memory. METHODS A C57BL/6 mouse model of diabetes was constructed by intraperitoneal injection of streptozotocin. The mice were randomly divided into 4 groups: the control group, diabetes group, diabetes + recombinantIL-22 (rIL-22) group and diabetes + IL-22BP group. The Morris water maze test was used to evaluate learning and memory, the expression of IL-22 was measured by ELISA, and Evans Blue staining was used to evaluate blood-brain barrier permeability. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) was used to measure the mRNA expression of IL-22 and IL-22Rα1 in the hippocampus. The morphology and number of hippocampal neurons were assessed by Nissl staining, and TUNEL staining was used to detect hippocampal neuronal apoptosis. Immunofluorescence was used to analyze IL-22Rα1 expression and localization in hippocampus, and Western blotting was used to evaluate the expression of IL-22, IL-22Rα1, IL-22BP, and the apoptosis related proteins Caspase-3 and C-caspase-3. RESULTS Compared with those in the control group, mice in the diabetes group showed cognitive decline; apoptosis of hippocampal neurons; increased expression of hippocampal Caspase-3, C-Caspase-3, IL-22, IL-22Rα1, and IL-22BP; and a decreased IL-22/IL-22BP ratio. Learning and memory were improved, neuronal apoptosis was attenuated, IL-22Rα1 expression and the IL-22/IL-22BP ratio were increased, and caspase-3 and C-caspase-3 expression was decreased in the rIL-22-treated group compared with the diabetes group. IL-22BP treatment aggravated diabetic cognitive dysfunction and pathological alterations in the hippocampus, decreased the IL-22/IL-22BP ratio, and increased the expression of caspase-3 and C-caspase-3 in mice with diabetes. CONCLUSION A decrease in the IL-22/IL-22BP ratio plays an important role in diabetic cognitive dysfunction, and rIL-22 can effectively alleviate DE. Herein, we shed light on the interaction between IL-22 and IL-22BP as therapeutic targets for DM.
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Affiliation(s)
- Xiaobai Wang
- Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China
| | - Shengxue Yu
- Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China
| | - Wenqiang Liu
- Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China
| | - Pan Lv
- Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China
| | - Lipan Zhao
- Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China
| | - Yufei Wang
- Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China
| | - Cong Fu
- Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China
| | - Lu Meng
- Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China
| | - Qi Yang
- Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China
| | - Xuehua Wang
- Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China
| | - Ying Huang
- Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China
| | - Zhongfu Zuo
- Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China.
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China.
- Department of Anatomy, Histology and Embryology, Postdoctoral Research Station, Guangxi Medical University, Nanning, China.
| | - Xuezheng Liu
- Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China.
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China.
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9
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Zhang K, Chen L, Zhu C, Zhang M, Liang C. Current Knowledge of Th22 Cell and IL-22 Functions in Infectious Diseases. Pathogens 2023; 12:pathogens12020176. [PMID: 36839448 PMCID: PMC9965464 DOI: 10.3390/pathogens12020176] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 01/19/2023] [Accepted: 01/19/2023] [Indexed: 01/24/2023] Open
Abstract
T helper 22 (Th22) cells, a newly defined CD4+ T-cell lineage, are characterized by their distinct cytokine profile, which primarily consists of IL-13, IL-22 and TNF-α. Th22 cells express a wide spectrum of chemokine receptors, such as CCR4, CCR6 and CCR10. The main effector molecule secreted by Th22 cells is IL-22, a member of the IL-10 family, which acts by binding to IL-22R and triggering a complex downstream signaling system. Th22 cells and IL-22 have been found to play variable roles in human immunity. In preventing the progression of infections such as HIV and influenza, Th22/IL-22 exhibited protective anti-inflammatory characteristics, and their deleterious proinflammatory activities have been demonstrated to exacerbate other illnesses, including hepatitis B and Helicobacter pylori infection. Herein, we review the current understanding of Th22 cells, including their definition, differentiation and mechanisms, and the effect of Th22/IL-22 on human infectious diseases. According to studies on Th22 cells, Th22/IL-22 may be a promising therapeutic target and an effective treatment strategy for various infections.
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Affiliation(s)
- Kunyu Zhang
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
- Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei 230022, China
- Institute of Urology, Anhui Medical University, Hefei 230022, China
- The Second Clinical Medical College, Anhui Medical University, Hefei 230032, China
| | - Lei Chen
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
- Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei 230022, China
- Institute of Urology, Anhui Medical University, Hefei 230022, China
| | - Chenyu Zhu
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
- Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei 230022, China
- Institute of Urology, Anhui Medical University, Hefei 230022, China
- The Second Clinical Medical College, Anhui Medical University, Hefei 230032, China
| | - Meng Zhang
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
- Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei 230022, China
- Institute of Urology, Anhui Medical University, Hefei 230022, China
- Correspondence: (M.Z.); (C.L.); Tel./Fax: +86-55162922034 (M.Z.); +86-55162922034 (C.L.)
| | - Chaozhao Liang
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
- Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei 230022, China
- Institute of Urology, Anhui Medical University, Hefei 230022, China
- Correspondence: (M.Z.); (C.L.); Tel./Fax: +86-55162922034 (M.Z.); +86-55162922034 (C.L.)
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10
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Madeshiya AK, Pillai A. Innate lymphoid cells in depression: Current status and perspectives. Biomark Neuropsychiatry 2022; 7. [PMID: 37123464 PMCID: PMC10136288 DOI: 10.1016/j.bionps.2022.100055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
The recent discovery of innate lymphoid cells (ILCs) has provided new insights into our understanding of the pathogenesis of many disease conditions with immune dysregulation. Type 1 innate lymphoid cells (ILC1s) induce type I immunity and are characterized by the expression of signature cytokine IFN-γ and the master transcription factor T-bet; ILC2s stimulate type II immune responses and are defined by the expression of signature cytokines IL-5 and IL-13, and transcription factors ROR-α and GATA3; ILC3s requires the transcription factor RORγt and produce IL-22 and IL-17. ILCs are largely tissue-resident and are enriched at barrier surfaces of the mammalian body. Increasing evidence shows that inflammation is involved in the pathogenesis of depression. Although few studies have directly investigated the role of ILCs in depression, several studies have examined the levels of cytokines produced by ILCs in depressed subjects. This review summarizes the potential roles of ILCs in depression. A better understanding of the biology of ILCs may lead to the development of new therapeutic strategies for the management of depression.
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11
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Lopez DV, Kongsbak‐Wismann M. Role of IL-22 in homeostasis and diseases of the skin. APMIS 2022; 130:314-322. [PMID: 35316548 PMCID: PMC9324963 DOI: 10.1111/apm.13221] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 03/21/2022] [Indexed: 11/28/2022]
Abstract
Interleukin-22 (IL-22) is a cytokine mainly produced by T cells and innate lymphoid cells (ILC). IL-22 primarily targets non-hematopoietic cells such as epithelial cells and fibroblasts. In the skin, IL-22 promotes the proliferation of keratinocytes and dermal fibroblasts. IL-22 furthermore regulates innate immune responses as it induces the production of antimicrobial proteins and neutrophil-attracting chemokines. IL-22 plays an important role in wound healing and in the protection against skin infections. However, IL-22 can also contribute to the pathogenesis of several inflammatory skin diseases such as psoriasis, atopic dermatitis and allergic contact dermatitis. In this review, current information regarding the structure, function and regulation of IL-22 is discussed with a special focus on the role of IL-22 in the skin and in skin diseases.
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Affiliation(s)
- Daniel Villalba Lopez
- The LEO Foundation Skin Immunology Research CenterDepartment of Immunology and MicrobiologyFaculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
| | - Martin Kongsbak‐Wismann
- The LEO Foundation Skin Immunology Research CenterDepartment of Immunology and MicrobiologyFaculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
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12
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Kim S, Hong EH, Lee CK, Ryu Y, Jeong H, Heo S, Lee JJ, Ko HJ. Amelioration of DSS-Induced Acute Colitis in Mice by Recombinant Monomeric Human Interleukin-22. Immune Netw 2022; 22:e26. [PMID: 35799707 PMCID: PMC9250870 DOI: 10.4110/in.2022.22.e26] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 02/22/2022] [Accepted: 03/03/2022] [Indexed: 12/13/2022] Open
Abstract
IL-22, a pleiotropic cytokine, is known to have a profound effect on the regeneration of damaged intestinal barriers. The tissue-protective properties of IL-22 are expected to be potentially exploited in the attenuation and treatment of colitis. However, because of the disease-promoting role of IL-22 in chronic inflammation, a comprehensive evaluation is required to translate IL-22 into the clinical domain. Here, we present the effective production of soluble human IL-22 in bacteria to prove whether recombinant IL-22 has the ability to ameliorate colitis and inflammation. IL-22 was expressed in the form of a biologically active monomer and non-functional oligomers. Monomeric IL-22 (mIL-22) was highly purified through a series of 3 separate chromatographic methods and an enzymatic reaction. We reveal that the resulting mIL-22 is correctly folded and is able to phosphorylate STAT3 in HT-29 cells. Subsequently, we demonstrate that mIL-22 enables the attenuation of dextran sodium sulfate-induced acute colitis in mice, as well as the suppression of pro-inflammatory cytokine production. Collectively, our results suggest that the recombinant mIL-22 is suitable to study the biological roles of endogenous IL-22 in immune responses and can be developed as a biological agent associated with inflammatory disorders.
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Affiliation(s)
- Suhyun Kim
- Department of Biochemistry, Kangwon National University, Chuncheon 24341, Korea
| | - Eun-Hye Hong
- Laboratory of Microbiology and Immunology, Department of Pharmacy, Kangwon National University, Chuncheon 24341, Korea
| | - Cheol-Ki Lee
- Department of Biochemistry, Kangwon National University, Chuncheon 24341, Korea
| | - Yiseul Ryu
- Institute of Life Sciences (ILS), Kangwon National University, Chuncheon 24341, Korea
| | - Hyunjin Jeong
- Laboratory of Microbiology and Immunology, Department of Pharmacy, Kangwon National University, Chuncheon 24341, Korea
| | - Seungnyeong Heo
- Department of Biochemistry, Kangwon National University, Chuncheon 24341, Korea
| | - Joong-Jae Lee
- Department of Biochemistry, Kangwon National University, Chuncheon 24341, Korea
- Institute of Life Sciences (ILS), Kangwon National University, Chuncheon 24341, Korea
- Global/Gangwon Innovative Biologics-Regional Leading Research Center (GIB-RLRC), Kangwon National University, Chuncheon 24341, Korea
| | - Hyun-Jeong Ko
- Laboratory of Microbiology and Immunology, Department of Pharmacy, Kangwon National University, Chuncheon 24341, Korea
- Global/Gangwon Innovative Biologics-Regional Leading Research Center (GIB-RLRC), Kangwon National University, Chuncheon 24341, Korea
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13
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Chen N, Xu Y, Mou J, Rao Q, Xing H, Tian Z, Tang K, Wang M, Wang J. Targeting of IL-10R on acute myeloid leukemia blasts with chimeric antigen receptor-expressing T cells. Blood Cancer J 2021; 11:144. [PMID: 34392305 PMCID: PMC8364556 DOI: 10.1038/s41408-021-00536-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 07/25/2021] [Accepted: 07/29/2021] [Indexed: 12/13/2022] Open
Abstract
Acute myeloid leukemia (AML) is a biologically and clinically heterogeneous disease with a dismal prognosis and limited treatment options. Chimeric antigen receptor (CAR) T cells have achieved unprecedented clinical responses in patients with B cell malignancies but a dismal consequences in AML. In our previous study, we found that interleukin-10 receptor (IL-10R) was overexpressed in most AML cells, and played an important role in promoting the stemness of leukemia cells. In this study, we developed a novel ligand-based CAR-T cell targeting IL-10R, which displayed striking cytotoxicity both in vitro and in vivo against AML cells. Except for monocytes, it had no significant adverse effects on the normal hematopoietic system, including CD34+ hematopoietic stem and progenitor cells (HSPCs). In addition, even though the incorporation of IL-10 in the CAR cassette led to phenotypes change, it had few adverse effects on the survival and biological activity of IL-10 CAR-T cells and did not cause excessive proliferation of leukemia cells. Therefore, we propose IL-10R is a novel promising therapeutic candidate for AML, and IL-10R targeted CAR-T therapy provides a new treatment strategy to improve the prognosis of AML.
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Affiliation(s)
- Nianci Chen
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China.,Tianjin Key Laboratory of Cell Therapy for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Yingxi Xu
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China.,Tianjin Key Laboratory of Cell Therapy for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Junli Mou
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China.,Tianjin Key Laboratory of Cell Therapy for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Qing Rao
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China.,Tianjin Key Laboratory of Cell Therapy for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Haiyan Xing
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China.,Tianjin Key Laboratory of Cell Therapy for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Zheng Tian
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China.,Tianjin Key Laboratory of Cell Therapy for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Kejing Tang
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China.,Tianjin Key Laboratory of Cell Therapy for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Min Wang
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China. .,Tianjin Key Laboratory of Cell Therapy for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China.
| | - Jiangxiang Wang
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China. .,Tianjin Key Laboratory of Cell Therapy for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China. .,National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China.
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14
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Luo JW, Hu Y, Liu J, Yang H, Huang P. Interleukin-22: a potential therapeutic target in atherosclerosis. Mol Med 2021; 27:88. [PMID: 34388961 PMCID: PMC8362238 DOI: 10.1186/s10020-021-00353-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 08/07/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Atherosclerosis is recognized as a chronic immuno-inflammatory disease that is characterized by the accumulation of immune cells and lipids in the vascular wall. In this review, we focus on the latest advance regarding the regulation and signaling pathways of IL-22 and highlight its impacts on atherosclerosis. MAIN BODY IL-22, an important member of the IL-10 family of cytokines, is released by cells of the adaptive and innate immune system and plays a key role in the development of inflammatory diseases. The binding of IL-22 to its receptor complex can trigger a diverse array of downstream signaling pathways, in particular the JAK/STAT, to induce the expression of chemokines and proinflammatory cytokines. Recently, numerous studies suggest that IL-22 is involved in the pathogenesis of atherosclerosis by regulation of VSMC proliferation and migration, angiogenesis, inflammatory response, hypertension, and cholesterol metabolism. CONCLUSION IL-22 promotes the development of atherosclerosis by multiple mechanisms, which may be a promising therapeutic target in the pathogenesis of atherosclerosis.
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Affiliation(s)
- Jin-Wen Luo
- Department of Cardio-Thoracic Surgery, Hunan Children's Hospital, Changsha, 410007, People's Republic of China
| | - Yuan Hu
- Department of Ultrasound Medicine, Hunan Children's Hospital, Changsha, 410007, People's Republic of China
| | - Jian Liu
- Department of Cardio-Thoracic Surgery, Hunan Children's Hospital, Changsha, 410007, People's Republic of China
| | - Huan Yang
- Department of Respiratory Medicine, Hunan Provincial People's Hospital, Changsha, Hunan, 410001, People's Republic of China.
| | - Peng Huang
- Department of Cardio-Thoracic Surgery, Hunan Children's Hospital, Changsha, 410007, People's Republic of China.
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15
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Zhang H, Chen M, Liu Y, Dong X, Zhang C, Jiang H, Chen X. Paroxetine combined with fluorouracil plays a therapeutic role in mouse models of colorectal cancer with depression through inhibiting IL-22 expression to regulate the MAPK signaling pathway. Exp Ther Med 2020; 20:240. [PMID: 33178338 PMCID: PMC7651781 DOI: 10.3892/etm.2020.9370] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Accepted: 08/14/2020] [Indexed: 12/12/2022] Open
Abstract
The objective of the present study was to observe the therapeutic effect of paroxetine combined with fluorouracil on mice with colorectal cancer (CRC) complicated with depression and to explore its mechanism of action. Using chronic mild stress and xenograft tumor methods to model CRC complicated with depression, 60 BALB/c mice were randomly divided into control, tumor model, tumor depression model, tumor depression antidepressant, tumor depression chemotherapy and tumor depression antidepressant plus chemotherapeutic drug groups. Changes in mouse sucrose preference and forced swimming tests were tracked. Changes in tumor volume and weight were compared, the tumor inhibition rate was calculated, Ki-67 expression in tumor tissues was detected using immunohistochemistry and IL-22 levels in peripheral blood were detected using ELISAs. Additionally, protein expression levels of IL-22, Bcl-2, Bax, caspase-3, p38, phosphorylated (p)-p38, ERK, p-ERK, JNK and p-JNK in tumor tissue were detected using western blotting. Following treatment with paroxetine and chemotherapy drugs, the sucrose preference index was increased, autonomic behavior dysfunction was alleviated and tumor growth was significantly inhibited. Furthermore, the expression levels of Ki-67 and apoptosis-related proteins, Bax and caspase-3, increased in tumor tissues, anti-apoptosis protein Bcl2 expression levels decreased significantly, IL-22 levels in the blood and tumor tissues were reduced and p-p38, p-ERK and p-JNK proteins were significantly reduced. It was concluded that paroxetine combined with chemotherapy drugs improved depressive behavior and promoted the survival state in a mouse model of CRC and depression, possibly through inhibiting IL-22 expression to regulate the activity of the MAPK signaling pathway.
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Affiliation(s)
- Huijie Zhang
- Department of Psychiatry, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Meixv Chen
- Department of Psychiatry, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Ying Liu
- Department of Psychiatry, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Xiaomei Dong
- Department of Psychiatry, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Chan Zhang
- Department of Psychiatry, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Han Jiang
- Department of Psychiatry, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Xue Chen
- Department of Psychiatry, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
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16
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Arshad T, Mansur F, Palek R, Manzoor S, Liska V. A Double Edged Sword Role of Interleukin-22 in Wound Healing and Tissue Regeneration. Front Immunol 2020; 11:2148. [PMID: 33042126 PMCID: PMC7527413 DOI: 10.3389/fimmu.2020.02148] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 08/07/2020] [Indexed: 12/14/2022] Open
Abstract
Wound healing and tissue regeneration is an intricate biological process that involves repair of cellular damage and maintenance of tissue integrity. Cascades involved in wound healing and tissue regeneration highly overlap with cancer causing pathways. Usually, subsequent tissue damage events include release of a number of cytokines to accomplish post-trauma restoration. IL-22 is one of the cytokines that are immediately produced to initiate immune response against several tissue impairments. IL-22 is a fundamental mediator in inflammation, mucous production, protective role against pathogens, wound healing, and tissue regeneration. However, accumulating evidence suggests pivotal role of IL-22 in instigation of various cancers due to its pro-inflammatory and tissue repairing activity. In this review, we summarize how healing effects of IL-22, when executed in an uncontrollable fashion can lead to carcinogenesis.
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Affiliation(s)
- Tanzeela Arshad
- Molecular Virology and Immunology Research Group, Atta-ur-Rahman School of Applied Bio-Sciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Fizzah Mansur
- Molecular Virology and Immunology Research Group, Atta-ur-Rahman School of Applied Bio-Sciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Richard Palek
- Department of Surgery, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czechia
- Laboratory of Cancer Treatment and Tissue Regeneration, Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Prague, Czechia
| | - Sobia Manzoor
- Molecular Virology and Immunology Research Group, Atta-ur-Rahman School of Applied Bio-Sciences, National University of Sciences and Technology, Islamabad, Pakistan
- Laboratory of Cancer Treatment and Tissue Regeneration, Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Prague, Czechia
| | - Vaclav Liska
- Department of Surgery, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czechia
- Laboratory of Cancer Treatment and Tissue Regeneration, Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Prague, Czechia
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17
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Gorby C, Sotolongo Bellón J, Wilmes S, Warda W, Pohler E, Fyfe PK, Cozzani A, Ferrand C, Walter MR, Mitra S, Piehler J, Moraga I. Engineered IL-10 variants elicit potent immunomodulatory effects at low ligand doses. Sci Signal 2020; 13:13/649/eabc0653. [PMID: 32934073 DOI: 10.1126/scisignal.abc0653] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Interleukin-10 (IL-10) is a dimeric cytokine with both immunosuppressive and immunostimulatory activities; however, IL-10-based therapies have shown only marginal clinical benefits. Here, we explored whether the stability of the IL-10 receptor complex contributes to the immunomodulatory potency of IL-10. We generated an IL-10 mutant with enhanced affinity for its IL-10Rβ receptor using yeast surface display. Compared to the wild-type cytokine, the affinity-enhanced IL-10 variants recruited IL-10Rβ more efficiently into active cell surface signaling complexes and triggered greater STAT1 and STAT3 activation in human monocytes and CD8+ T cells. These effects, in turn, led to more robust induction of IL-10-mediated gene expression programs at low ligand concentrations in both human cell subsets. IL-10-regulated genes are involved in monocyte energy homeostasis, migration, and trafficking and in CD8+ T cell exhaustion. At nonsaturating doses, IL-10 did not induce key components of its gene expression program, which may explain its lack of efficacy in clinical settings. Our engineered IL-10 variant showed a more robust bioactivity profile than that of wild-type IL-10 at low doses in monocytes and CD8+ T cells. Moreover, CAR-modified T cells expanded with the engineered IL-10 variant displayed superior cytolytic activity than those expanded with wild-type IL-10. Our study provides insights into how IL-10 receptor complex stability fine-tunes IL-10 biology and opens new opportunities to revitalize failed IL-10 therapies.
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Affiliation(s)
- Claire Gorby
- Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee DD15EH, UK
| | - Junel Sotolongo Bellón
- Department of Biology and Center for Cellular Nanoanalytics (CellNanOs), University of Osnabrück, Barbarastraße 11, 49076 Osnabrück, Germany
| | - Stephan Wilmes
- Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee DD15EH, UK
| | - Walid Warda
- Université Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, F-25000 Besançon, France
| | - Elizabeth Pohler
- Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee DD15EH, UK
| | - Paul K Fyfe
- Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee DD15EH, UK
| | - Adeline Cozzani
- Université de Lille, INSERM UMR1277 CNRS UMR9020-CANTHER and Institut pour la Recherche sur le Cancer de Lille (IRCL), Lille, France
| | - Christophe Ferrand
- Université Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, F-25000 Besançon, France
| | - Mark R Walter
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35243, USA
| | - Suman Mitra
- Université de Lille, INSERM UMR1277 CNRS UMR9020-CANTHER and Institut pour la Recherche sur le Cancer de Lille (IRCL), Lille, France
| | - Jacob Piehler
- Department of Biology and Center for Cellular Nanoanalytics (CellNanOs), University of Osnabrück, Barbarastraße 11, 49076 Osnabrück, Germany
| | - Ignacio Moraga
- Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee DD15EH, UK.
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18
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Mossner S, Kuchner M, Fazel Modares N, Knebel B, Al-Hasani H, Floss DM, Scheller J. Synthetic interleukin 22 (IL-22) signaling reveals biological activity of homodimeric IL-10 receptor 2 and functional cross-talk with the IL-6 receptor gp130. J Biol Chem 2020; 295:12378-12397. [PMID: 32611765 PMCID: PMC7458808 DOI: 10.1074/jbc.ra120.013927] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 06/22/2020] [Indexed: 12/22/2022] Open
Abstract
Cytokine signaling is transmitted by cell-surface receptors that function as biological switches controlling mainly immune-related processes. Recently, we have designed synthetic cytokine receptors (SyCyRs) consisting of GFP and mCherry nanobodies fused to transmembrane and intracellular domains of cytokine receptors that phenocopy cytokine signaling induced by nonphysiological homo- and heterodimeric GFP-mCherry ligands. Interleukin 22 (IL-22) signals via both IL-22 receptor α1 (IL-22Rα1) and the common IL-10R2, belongs to the IL-10 cytokine family, and is critically involved in tissue regeneration. Here, IL-22 SyCyRs phenocopied native IL-22 signal transduction, indicated by induction of cytokine-dependent cellular proliferation, signal transduction, and transcriptome analysis. Whereas homodimeric IL-22Rα1 SyCyRs failed to activate signaling, homodimerization of the second IL-22 signaling chain, SyCyR(IL-10R2), which previously was considered not to induce signal transduction, led to induction of signal transduction. Interestingly, the SyCyR(IL-10R2) and SyCyR(IL-22Rα1) constructs could form functional heterodimeric receptor signaling complexes with the synthetic IL-6 receptor chain SyCyR(gp130). In summary, we have demonstrated that IL-22 signaling can be phenocopied by synthetic cytokine receptors, identified a functional IL-10R2 homodimeric receptor complex, and uncovered broad receptor cross-talk of IL-22Rα1 and IL-20R2 with gp130.
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Affiliation(s)
- Sofie Mossner
- Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Marcus Kuchner
- Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Nastaran Fazel Modares
- Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Birgit Knebel
- Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Hadi Al-Hasani
- Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Doreen M Floss
- Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Jürgen Scheller
- Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
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19
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Nguyen HMH, Torres JA, Agrawal S, Agrawal A. Nicotine Impairs the Response of Lung Epithelial Cells to IL-22. Mediators Inflamm 2020; 2020:6705428. [PMID: 32189996 PMCID: PMC7066416 DOI: 10.1155/2020/6705428] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Revised: 01/11/2020] [Accepted: 02/05/2020] [Indexed: 02/07/2023] Open
Abstract
Smoking is a major risk factor for pulmonary diseases that include chronic obstructive pulmonary diseases (COPD) and cancer. Nicotine is the toxic and addictive component of tobacco products, like cigarettes, that negatively affects the immune system. Here, we examined the effect of nicotine on the IL-22 pathway that protects lung function by increasing transepithelial resistance and epithelial cell regeneration and repair. Our results indicate that exposure to nicotine impairs the regenerative capacity of primary bronchial epithelial cells in scratch assays. IL-22 at 100 ng/ml significantly improved wound healing in epithelial cells; however, the exposure to nicotine hampered the IL-22-mediated effect of wound healing. Investigation into the mechanisms showed that IL-22 receptor, IL-22Rα1, was downregulated in the presence of nicotine as determined by q-PCR and flow cytometry. We also investigated the effect of nicotine on IL-22 production by T cells. Results indicate that nicotine inhibited the secretion of IL-22 from T cells in response to aryl hydrocarbon receptor (AHR) ligand, FICZ. Altogether, the data suggests that nicotine negatively influences the IL-22-IL-22R axis. This impairment may contribute to the nicotine-mediated detrimental effects on lung function.
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Affiliation(s)
- Hannah My-Hanh Nguyen
- Division of Basic and Clinical Immunology, Department of Medicine, University of California, Irvine, Irvine, CA 92697, USA
| | - Jaclene Amber Torres
- Division of Basic and Clinical Immunology, Department of Medicine, University of California, Irvine, Irvine, CA 92697, USA
| | - Sudhanshu Agrawal
- Division of Basic and Clinical Immunology, Department of Medicine, University of California, Irvine, Irvine, CA 92697, USA
| | - Anshu Agrawal
- Division of Basic and Clinical Immunology, Department of Medicine, University of California, Irvine, Irvine, CA 92697, USA
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20
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Gómez-Fernández P, Lopez de Lapuente Portilla A, Astobiza I, Mena J, Urtasun A, Altmann V, Matesanz F, Otaegui D, Urcelay E, Antigüedad A, Malhotra S, Montalban X, Castillo-Triviño T, Espino-Paisán L, Aktas O, Buttmann M, Chan A, Fontaine B, Gourraud PA, Hecker M, Hoffjan S, Kubisch C, Kümpfel T, Luessi F, Zettl UK, Zipp F, Alloza I, Comabella M, Lill CM, Vandenbroeck K. The Rare IL22RA2 Signal Peptide Coding Variant rs28385692 Decreases Secretion of IL-22BP Isoform-1, -2 and -3 and Is Associated with Risk for Multiple Sclerosis. Cells 2020; 9:cells9010175. [PMID: 31936765 PMCID: PMC7017210 DOI: 10.3390/cells9010175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Revised: 12/29/2019] [Accepted: 01/03/2020] [Indexed: 10/29/2022] Open
Abstract
The IL22RA2 locus is associated with risk for multiple sclerosis (MS) but causative variants are yet to be determined. In a single nucleotide polymorphism (SNP) screen of this locus in a Basque population, rs28385692, a rare coding variant substituting Leu for Pro at position 16 emerged significantly (p = 0.02). This variant is located in the signal peptide (SP) shared by the three secreted protein isoforms produced by IL22RA2 (IL-22 binding protein-1(IL-22BPi1), IL-22BPi2 and IL-22BPi3). Genotyping was extended to a Europe-wide case-control dataset and yielded high significance in the full dataset (p = 3.17 × 10-4). Importantly, logistic regression analyses conditioning on the main known MS-associated SNP at this locus, rs17066096, revealed that this association was independent from the primary association signal in the full case-control dataset. In silico analysis predicted both disruption of the alpha helix of the H-region of the SP and decreased hydrophobicity of this region, ultimately affecting the SP cleavage site. We tested the effect of the p.Leu16Pro variant on the secretion of IL-22BPi1, IL-22BPi2 and IL-22BPi3 and observed that the Pro16 risk allele significantly lowers secretion levels of each of the isoforms to around 50%-60% in comparison to the Leu16 reference allele. Thus, our study suggests that genetically coded decreased levels of IL-22BP isoforms are associated with augmented risk for MS.
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Affiliation(s)
- Paloma Gómez-Fernández
- Neurogenomiks Laboratory, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain; (P.G.-F.); (A.L.d.L.P.); (I.A.); (J.M.); (A.U.); (I.A.)
| | - Aitzkoa Lopez de Lapuente Portilla
- Neurogenomiks Laboratory, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain; (P.G.-F.); (A.L.d.L.P.); (I.A.); (J.M.); (A.U.); (I.A.)
- Department of Laboratory Medicine, Lund University, SE-221 00 Lund, Sweden
| | - Ianire Astobiza
- Neurogenomiks Laboratory, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain; (P.G.-F.); (A.L.d.L.P.); (I.A.); (J.M.); (A.U.); (I.A.)
| | - Jorge Mena
- Neurogenomiks Laboratory, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain; (P.G.-F.); (A.L.d.L.P.); (I.A.); (J.M.); (A.U.); (I.A.)
- Inflammation & Biomarkers Group, Biocruces Bizkaia Health Research Institute, 48903 Barakaldo, Spain
| | - Andoni Urtasun
- Neurogenomiks Laboratory, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain; (P.G.-F.); (A.L.d.L.P.); (I.A.); (J.M.); (A.U.); (I.A.)
| | - Vivian Altmann
- Genetic and Molecular Epidemiology Group, Lübeck Platform for Genome Analytics, Institutes of Neurogenetics and Cardiogenetics, University of Lübeck, 23552 Lübeck, Germany; (V.A.); (C.M.L.)
| | - Fuencisla Matesanz
- Department of Cell Biology and Immunology, Instituto de Parasitología y Biomedicina López Neyra (IPBLN), CSIC, 18002 Granada, Spain;
| | - David Otaegui
- Multiple Sclerosis Group, Biodonostia Research Institute, Paseo Doctor Begiristain, s/n, 20014 San Sebastián, Spain; (D.O.); (T.C.-T.)
| | - Elena Urcelay
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, IdISSC, 28014 Madrid, Spain; (E.U.); (L.E.-P.)
| | | | - Sunny Malhotra
- Servei de Neurologia-Neuroimmunologia, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d’Hebron (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, 08007 Barcelona, Spain; (S.M.); (X.M.); (M.C.)
| | - Xavier Montalban
- Servei de Neurologia-Neuroimmunologia, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d’Hebron (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, 08007 Barcelona, Spain; (S.M.); (X.M.); (M.C.)
| | - Tamara Castillo-Triviño
- Multiple Sclerosis Group, Biodonostia Research Institute, Paseo Doctor Begiristain, s/n, 20014 San Sebastián, Spain; (D.O.); (T.C.-T.)
| | - Laura Espino-Paisán
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, IdISSC, 28014 Madrid, Spain; (E.U.); (L.E.-P.)
| | - Orhan Aktas
- Department of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany;
| | - Mathias Buttmann
- Department of Neurology, University of Wuerzburg, 97080 Wuerzburg, Germany;
- Department of Neurology, Caritas Hospital, 97980 Bad Mergentheim, Germany
| | - Andrew Chan
- Department of Neurology, Inselspital Bern, Bern University Hospital, University of Bern, 3011 Bern, Switzerland;
| | - Bertrand Fontaine
- INSERM, Sorbonne University, Assistance Publique-Hopitaux de Paris (AP-HP), UMR 974 and Neuro-Myology Service, University Hospital Pitié-Salpêtrière, 75013 Paris, France;
| | - Pierre-Antoine Gourraud
- Nantes Université, CHU, INSERM, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ATIP-Avenir, Equipe 5, 44093 Nantes, France;
- CHU de Nantes, INSERM, CIC 1413, Pôle Hospitalo-Universitaire 11: Santé Publique, Clinique des données, 44000 Nantes, France
| | - Michael Hecker
- Department of Neurology, Neuroimmunological Section, University of Rostock, 18147 Rostock, Germany; (M.H.); (U.K.Z.)
| | - Sabine Hoffjan
- Department of Human Genetics, Ruhr-University Bochum, 44801 Bochum, Germany;
| | - Christian Kubisch
- Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany;
| | - Tania Kümpfel
- Institute of Clinical Neuroimmunology, Ludwig-Maximilians University, 80333 Munich, Germany;
| | - Felix Luessi
- Department of Neurology, Focus Program Translational Neuroscience, University Medical Center of the Johannes Gutenberg University Mainz, 55116 Mainz, Germany; (F.L.); (F.Z.)
| | - Uwe K. Zettl
- Department of Neurology, Neuroimmunological Section, University of Rostock, 18147 Rostock, Germany; (M.H.); (U.K.Z.)
| | - Frauke Zipp
- Department of Neurology, Focus Program Translational Neuroscience, University Medical Center of the Johannes Gutenberg University Mainz, 55116 Mainz, Germany; (F.L.); (F.Z.)
| | - Iraide Alloza
- Neurogenomiks Laboratory, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain; (P.G.-F.); (A.L.d.L.P.); (I.A.); (J.M.); (A.U.); (I.A.)
- Inflammation & Biomarkers Group, Biocruces Bizkaia Health Research Institute, 48903 Barakaldo, Spain
| | - Manuel Comabella
- Servei de Neurologia-Neuroimmunologia, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d’Hebron (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, 08007 Barcelona, Spain; (S.M.); (X.M.); (M.C.)
| | - Christina M. Lill
- Genetic and Molecular Epidemiology Group, Lübeck Platform for Genome Analytics, Institutes of Neurogenetics and Cardiogenetics, University of Lübeck, 23552 Lübeck, Germany; (V.A.); (C.M.L.)
- Department of Neurology, Focus Program Translational Neuroscience, University Medical Center of the Johannes Gutenberg University Mainz, 55116 Mainz, Germany; (F.L.); (F.Z.)
- Section for Translational Surgical Oncology and Biobanking, Department of Surgery, University of Lübeck and University Medical Center Schleswig-Holstein, Campus Lübeck, 23552 Lübeck, Germany
- Ageing Epidemiology Research Unit, School of Public Health, Imperial College, London SW71, UK
| | - Koen Vandenbroeck
- Neurogenomiks Laboratory, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain; (P.G.-F.); (A.L.d.L.P.); (I.A.); (J.M.); (A.U.); (I.A.)
- Inflammation & Biomarkers Group, Biocruces Bizkaia Health Research Institute, 48903 Barakaldo, Spain
- Ikerbasque, Basque Foundation for Science, 48013 Bilbao, Spain
- Correspondence: ; Tel.: +34-946182622 (ext. 844748)
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21
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Morris R, Kershaw NJ, Babon JJ. The molecular details of cytokine signaling via the JAK/STAT pathway. Protein Sci 2019; 27:1984-2009. [PMID: 30267440 DOI: 10.1002/pro.3519] [Citation(s) in RCA: 574] [Impact Index Per Article: 95.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Revised: 09/24/2018] [Accepted: 09/24/2018] [Indexed: 12/21/2022]
Abstract
More than 50 cytokines signal via the JAK/STAT pathway to orchestrate hematopoiesis, induce inflammation and control the immune response. Cytokines are secreted glycoproteins that act as intercellular messengers, inducing proliferation, differentiation, growth, or apoptosis of their target cells. They act by binding to specific receptors on the surface of target cells and switching on a phosphotyrosine-based intracellular signaling cascade initiated by kinases then propagated and effected by SH2 domain-containing transcription factors. As cytokine signaling is proliferative and often inflammatory, it is tightly regulated in terms of both amplitude and duration. Here we review molecular details of the cytokine-induced signaling cascade and describe the architectures of the proteins involved, including the receptors, kinases, and transcription factors that initiate and propagate signaling and the regulatory proteins that control it.
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Affiliation(s)
- Rhiannon Morris
- Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, 3052, Victoria, Australia.,Department of Medical Biology, The University of Melbourne, Royal Parade, Parkville, 3050, Victoria, Australia
| | - Nadia J Kershaw
- Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, 3052, Victoria, Australia.,Department of Medical Biology, The University of Melbourne, Royal Parade, Parkville, 3050, Victoria, Australia
| | - Jeffrey J Babon
- Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, 3052, Victoria, Australia.,Department of Medical Biology, The University of Melbourne, Royal Parade, Parkville, 3050, Victoria, Australia
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22
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Fukaya T, Fukui T, Uto T, Takagi H, Nasu J, Miyanaga N, Arimura K, Nakamura T, Koseki H, Choijookhuu N, Hishikawa Y, Sato K. Pivotal Role of IL-22 Binding Protein in the Epithelial Autoregulation of Interleukin-22 Signaling in the Control of Skin Inflammation. Front Immunol 2018; 9:1418. [PMID: 29977242 PMCID: PMC6021537 DOI: 10.3389/fimmu.2018.01418] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Accepted: 06/06/2018] [Indexed: 12/12/2022] Open
Abstract
Disruption of skin homeostasis can lead to inflammatory cutaneous diseases resulting from the dysregulated interplay between epithelial keratinocytes and immune cells. Interleukin (IL)-22 signaling through membrane-bound IL-22 receptor 1 (IL-22R1) is crucial to maintain cutaneous epithelial integrity, and its malfunction mediates deleterious skin inflammation. While IL-22 binding protein (IL-22BP) binds IL-22 to suppress IL-22 signaling, how IL-22BP controls epithelial functionality to prevent skin inflammation remains unclear. Here, we describe the pivotal role of IL-22BP in mediating epithelial autoregulation of IL-22 signaling for the control of cutaneous pathogenesis. Unlike prominent expression of IL-22BP in dendritic cells in lymphoid tissues, epidermal keratinocytes predominantly expressed IL-22BP in the skin in the steady state, whereas its expression decreased during the development of psoriatic inflammation. Deficiency in IL-22BP aggravates psoriasiform dermatitis, accompanied by abnormal hyperproliferation of keratinocytes and excessive cutaneous inflammation as well as enhanced dermal infiltration of granulocytes and γδT cells. Furthermore, IL-22BP abrogates the functional alternations of keratinocytes upon stimulation with IL-22. On the other hand, treatment with IL-22BP alleviates the severity of cutaneous pathology and inflammation in psoriatic mice. Thus, the fine-tuning of IL-22 signaling through autocrine IL-22BP production in keratinocytes is instrumental in the maintenance of skin homeostasis.
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Affiliation(s)
- Tomohiro Fukaya
- Division of Immunology, Department of Infectious Diseases, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.,Japan Agency for Medical Research and Development (AMED), Tokyo, Japan
| | - Takehito Fukui
- Division of Immunology, Department of Infectious Diseases, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.,Department of Oral and Maxillofacial Surgery, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Tomofumi Uto
- Division of Immunology, Department of Infectious Diseases, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.,Japan Agency for Medical Research and Development (AMED), Tokyo, Japan
| | - Hideaki Takagi
- Division of Immunology, Department of Infectious Diseases, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.,Japan Agency for Medical Research and Development (AMED), Tokyo, Japan
| | - Junta Nasu
- Division of Immunology, Department of Infectious Diseases, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.,Department of Oral and Maxillofacial Surgery, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Noriaki Miyanaga
- Division of Immunology, Department of Infectious Diseases, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.,Department of Otolaryngology, Head and Neck Surgery, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Keiichi Arimura
- Division of Immunology, Department of Infectious Diseases, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.,Department of Oral and Maxillofacial Surgery, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Takeshi Nakamura
- Division of Immunology, Department of Infectious Diseases, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.,Department of Otolaryngology, Head and Neck Surgery, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Haruhiko Koseki
- Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Narantsog Choijookhuu
- Division of Histochemistry and Cell Biology, Department of Anatomy, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Yoshitaka Hishikawa
- Division of Histochemistry and Cell Biology, Department of Anatomy, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Katsuaki Sato
- Division of Immunology, Department of Infectious Diseases, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.,Japan Agency for Medical Research and Development (AMED), Tokyo, Japan
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23
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Xuan X, Tian Z, Zhang M, Zhou J, Gao W, Zhang Y, Zhang Y, Lei B, Ni B, Wu Y, Fan W. Diverse effects of interleukin-22 on pancreatic diseases. Pancreatology 2018; 18:231-237. [PMID: 29502986 DOI: 10.1016/j.pan.2018.02.014] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Revised: 02/20/2018] [Accepted: 02/23/2018] [Indexed: 12/11/2022]
Abstract
Interleukin-22 (IL-22) is involved in the development of lymphocytes and serves as a rapid and early source of the effector cytokines that are released in response to pathogen-induced changes in the microenvironment. Recent research has implicated IL-22 as a potential contributing factor to the spectrum of inflammation-related pancreatic diseases, particularly pancreatitis, fibrosis, carcinoma and diabetes. In this review, we summarize the current knowledge on the roles of IL-22 in the various pancreatic pathogenesis, providing insights into the underlying cellular and signaling mechanisms that will help guide future research into promising interventional targets with therapeutic potential.
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Affiliation(s)
- Xiuyun Xuan
- Department of Pathophysiology, Third Military Medical University, Chongqing, 400038, China; Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, 030200, China
| | - Zhiqiang Tian
- Institute of Immunology, PLA, Third Military Medical University, Chongqing, 400038, China
| | - Mengjie Zhang
- Department of Pathophysiology, Third Military Medical University, Chongqing, 400038, China
| | - Jian Zhou
- Department of Pathophysiology, Third Military Medical University, Chongqing, 400038, China
| | - Weiwu Gao
- Department of Pathophysiology, Third Military Medical University, Chongqing, 400038, China
| | - Yi Zhang
- Department of Pathophysiology, Third Military Medical University, Chongqing, 400038, China
| | - Yue Zhang
- Department of Dermatology, 105th Hospital of PLA, Bengbu Medical College, Hefei, 230001, China
| | - Bo Lei
- Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, 030200, China
| | - Bing Ni
- Department of Pathophysiology, Third Military Medical University, Chongqing, 400038, China
| | - Yuzhang Wu
- Institute of Immunology, PLA, Third Military Medical University, Chongqing, 400038, China.
| | - Weiping Fan
- Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, 030200, China.
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24
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Shabgah AG, Navashenaq JG, Shabgah OG, Mohammadi H, Sahebkar A. Interleukin-22 in human inflammatory diseases and viral infections. Autoimmun Rev 2017; 16:1209-1218. [PMID: 29037907 DOI: 10.1016/j.autrev.2017.10.004] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Accepted: 08/08/2017] [Indexed: 12/24/2022]
Abstract
Interleukin-22 (IL22) is one of the members of IL10 family. Elevated levels of this cytokine can be seen in diseases caused by T lymphocytes, such as Psoriasis, Rheumatoid arthritis, interstitial lung diseases. IL22 is produced by different cells in both innate and acquired immunities. Different types of T cells are able to produce IL22, but the major IL22-producing T-cell is the TCD4. TH22 cell is a new line of TCD4 cells, which differentiated from naive T cells in the presence of TNFα and IL6; 50% of peripheral blood IL22 is produced by these cells. IL22 has important functions in host defense at mucosal surfaces as well as in tissue repair. In this review, we assess the current understanding of this cytokine and focus on the possible roles of IL-22 in autoimmune diseases.
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Affiliation(s)
- Arezoo Gowhari Shabgah
- Immunology Research Center, Avicenna Research Institute, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Blood Borne Infections Research Center, AcademicCenter for Education, Culture and Research (ACECR), Razavi Khorasan Branch,Mashhad, Iran
| | - Jamshid Gholizadeh Navashenaq
- Immunology Research Center, Avicenna Research Institute, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Omid Gohari Shabgah
- Parasitology Department, Medical sciencesfaculty, Tarbiat Modares University, Tehran, Iran
| | - Hamed Mohammadi
- ImmunologyResearch Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amirhossein Sahebkar
- BiotechnologyResearch Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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25
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Carmo RF, Cavalcanti MSM, Moura P. Role of Interleukin-22 in chronic liver injury. Cytokine 2017; 98:107-114. [PMID: 27816383 DOI: 10.1016/j.cyto.2016.08.023] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2016] [Revised: 08/05/2016] [Accepted: 08/23/2016] [Indexed: 12/12/2022]
Abstract
Liver fibrosis is the result of an exacerbated wound-healing response associated with chronic liver injury. Advanced liver fibrosis results in cirrhosis, liver failure, and portal hypertension and frequently requires liver transplantation. The host immune response has an important role driving fibrosis deposition by activating hepatic stellate cells (HSCs). Interleukin-22 (IL-22) is a cytokine that plays a key role in promoting antimicrobial immunity and tissue repair at barrier surfaces. Data from literature suggest that IL-22 has a protective role in the liver by reducing fibrosis in some pathological conditions, however the results are contradictory. This review highlights current knowledge of IL-22' role in chronic liver injury, as well as its therapeutic potential for the treatment of chronic liver injury.
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Affiliation(s)
- Rodrigo F Carmo
- Colegiado de Farmácia, Universidade Federal do Vale do São Francisco (UNIVASF), Petrolina, Brazil.
| | - Maria S M Cavalcanti
- Instituto de Ciências Biológicas, Universidade de Pernambuco (UPE), Recife, Brazil
| | - Patrícia Moura
- Instituto de Ciências Biológicas, Universidade de Pernambuco (UPE), Recife, Brazil
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26
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La Manna S, Scognamiglio PL, Di Natale C, Leone M, Mercurio FA, Malfitano AM, Cianfarani F, Madonna S, Caravella S, Albanesi C, Novellino E, Marasco D. Characterization of linear mimetic peptides of Interleukin-22 from dissection of protein interfaces. Biochimie 2017; 138:106-115. [PMID: 28479106 DOI: 10.1016/j.biochi.2017.05.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2017] [Accepted: 05/02/2017] [Indexed: 12/12/2022]
Abstract
Interleukin-22 (IL-22) belongs to the family of IL-10 cytokines and is involved in a wide number of human diseases, including inflammatory disorders and cancer pathology. The ligand-receptor complex IL-22/IL-22R plays a key role in several pathways especially in the regulation and resolution of immune responses. The identification of novel compounds able to modulate IL-22/IL-22R complex could open the route to new therapeutic strategies in multiple human diseases. In this study, we designed and characterized IL-22 derived peptides at protein interface regions: several sequences revealed able to interfere with the protein complex with IC50 in the micromolar range as evaluated through Surface Plasmon Resonance (SPR) experiments. Their conformational characterization was carried out through Circular Dichroism (CD) and Nuclear Magnetic Resonance (NMR) spectroscopies, shedding new light into the features of IL-22 fragments and on structural determinants of IL-22/IL-22R1 recognition. Finally, several peptides were tested on human keratinocyte cultures for evaluating their ability to mimic the activation of molecular pathways downstream to IL-22R in response to IL-22 binding.
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Affiliation(s)
- Sara La Manna
- Department of Pharmacy, CIRPEB: Centro Interuniversitario di Ricerca sui Peptidi Bioattivi, University of Naples "Federico II", 80134, Naples, Italy
| | - Pasqualina Liana Scognamiglio
- Department of Pharmacy, CIRPEB: Centro Interuniversitario di Ricerca sui Peptidi Bioattivi, University of Naples "Federico II", 80134, Naples, Italy
| | - Concetta Di Natale
- Department of Pharmacy, CIRPEB: Centro Interuniversitario di Ricerca sui Peptidi Bioattivi, University of Naples "Federico II", 80134, Naples, Italy
| | - Marilisa Leone
- Institute of Biostructures and Bioimaging, CNR, 80134, Naples, Italy
| | | | - Anna Maria Malfitano
- Department of Pharmacy, CIRPEB: Centro Interuniversitario di Ricerca sui Peptidi Bioattivi, University of Naples "Federico II", 80134, Naples, Italy
| | - Francesca Cianfarani
- Laboratory of Cellular and Molecular Biology, Fondazione "Luigi Maria Monti", Istituto Dermopatico dell'Immacolata (IDI), IRCCS, Via Monti di Creta, 104, 00167, Rome, Italy
| | - Stefania Madonna
- Laboratory of Experimental Immunology, Fondazione "Luigi Maria Monti", Istituto Dermopatico dell'Immacolata (IDI), IRCCS, Via Monti di Creta, 104, 00167, Rome, Italy
| | - Sergio Caravella
- Laboratory of Experimental Immunology, Fondazione "Luigi Maria Monti", Istituto Dermopatico dell'Immacolata (IDI), IRCCS, Via Monti di Creta, 104, 00167, Rome, Italy
| | - Cristina Albanesi
- Laboratory of Experimental Immunology, Fondazione "Luigi Maria Monti", Istituto Dermopatico dell'Immacolata (IDI), IRCCS, Via Monti di Creta, 104, 00167, Rome, Italy
| | - Ettore Novellino
- Department of Pharmacy, CIRPEB: Centro Interuniversitario di Ricerca sui Peptidi Bioattivi, University of Naples "Federico II", 80134, Naples, Italy
| | - Daniela Marasco
- Department of Pharmacy, CIRPEB: Centro Interuniversitario di Ricerca sui Peptidi Bioattivi, University of Naples "Federico II", 80134, Naples, Italy.
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Wu Z, Hu Z, Cai X, Ren W, Dai F, Liu H, Chang J, Li B. Interleukin 22 attenuated angiotensin II induced acute lung injury through inhibiting the apoptosis of pulmonary microvascular endothelial cells. Sci Rep 2017; 7:2210. [PMID: 28526849 PMCID: PMC5438354 DOI: 10.1038/s41598-017-02056-w] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Accepted: 04/06/2017] [Indexed: 01/30/2023] Open
Abstract
Apoptosis of pulmonary microvascular endothelial cells (PMVECs) was considered to be closely related to the pathogenesis of acute lung injury (ALI). We aim to investigate whether IL-22 plays protective roles in lung injury through inhibiting the apoptosis of PMVECs. ALI model was induced through subcutaneous infusion of angiotensin II (Ang II). Lung injury and infiltration of inflammatory cells were evaluated by determining the PaO2/FiO2, calculation of dry to weight ratio in lung, and immunohistochemisty analysis. Apoptosis of PMVECs was determined using TUNEL assay and flow cytometry, respectively. Immunofluorescence and Western blot analysis were used to determine the expression and localization of STAT3, as well as the nucleus transmission of STAT3 from cytoplasm after IL22 treatment. Pathological findings showed ALI was induced 1 week after AngII infusion. IL22 inhibited the AngII-induced ALI, attenuated the edema in lung and the infiltration of inflammatory cells. Also, it contributed to the apoptosis of PMVECs induced by AngII. Meanwhile, significant increase was noticed in the expression of STAT3, phosphorylation of Y705-STAT3, and migration from cytoplasm to the nucleus after IL-22 treatment (P < 0.05). The activation of STAT3 by IL22 showed significant attenuation after AG490 treatment. Our data indicated that IL22 showed protective effects on lung injury through inhibiting the AngII-induced PMVECs apoptosis and PMVEC barrier injury by activating the JAK2/STAT3 signaling pathway.
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Affiliation(s)
- Zhiyong Wu
- Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, China.
| | - Zhipeng Hu
- Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, China
| | - Xin Cai
- Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, China
| | - Wei Ren
- Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, China
| | - Feifeng Dai
- Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, China
| | - Huagang Liu
- Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, China
| | - Jinxing Chang
- Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, China
| | - Bowen Li
- Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, China
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Khawar MB, Azam F, Sheikh N, Abdul Mujeeb K. How Does Interleukin-22 Mediate Liver Regeneration and Prevent Injury and Fibrosis? J Immunol Res 2016; 2016:2148129. [PMID: 28050571 PMCID: PMC5168458 DOI: 10.1155/2016/2148129] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Revised: 10/13/2016] [Accepted: 10/25/2016] [Indexed: 12/20/2022] Open
Abstract
Interleukin-22 (IL-22) is a pluripotent T cell-derived cytokine which is a member of IL-10 cytokine family. It is the only interleukin produced by immune cells but does not target immune system components. IL-22 is mainly produced by dendritic cells (DCs) and TH17, TH22, NK, and NKT cells and targets a number of body tissues including liver, pancreas, and other epithelial tissues. It provokes a series of downstream signaling pathways upon binding with IL-22R complex which protects liver damage through STAT3 activation. IL-22BP is an inhibitor of IL-22 which has 20-1000x more affinity to bind with IL-22 compared to IL-22R1 that inhibits IL-22 activity. Its level was found to be positively correlated with the severity of liver damage and fibrosis. So, the present review is an effort to reveal the exact mechanism lying in the hepatoprotective activity of IL-22 and some of its future therapeutic implications.
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Affiliation(s)
- Muhammad Babar Khawar
- Cell & Molecular Biology Lab, Department of Zoology, University of the Punjab, Lahore, Pakistan
| | - Fareeha Azam
- Cell & Molecular Biology Lab, Department of Zoology, University of the Punjab, Lahore, Pakistan
| | - Nadeem Sheikh
- Cell & Molecular Biology Lab, Department of Zoology, University of the Punjab, Lahore, Pakistan
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29
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Valeri M, Raffatellu M. Cytokines IL-17 and IL-22 in the host response to infection. Pathog Dis 2016; 74:ftw111. [PMID: 27915228 PMCID: PMC5975231 DOI: 10.1093/femspd/ftw111] [Citation(s) in RCA: 136] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Revised: 09/13/2016] [Accepted: 11/17/2016] [Indexed: 12/12/2022] Open
Abstract
Cytokines IL-17 and IL-22 play pivotal roles in host defense against microbes and in the development of chronic inflammatory diseases. These cytokines are produced by cells that are often located in epithelial barriers, including subsets of T cells and innate lymphoid cells. In general, IL-17 and IL-22 can be characterized as important cytokines in the rapid response to infectious agents, both by recruiting neutrophils and by inducing the production of antimicrobial peptides. Although each cytokine induces an innate immune response in epithelial cells, their functional spectra are generally distinct: IL-17 mainly induces an inflammatory tissue response and is involved in the pathogenesis of several autoimmune diseases, whereas IL-22 is largely protective and regenerative. In this review, we compare IL-17 and IL-22, describing overlaps and differences in their cellular sources as well as their regulation, signaling, biological functions and roles during disease, with a focus on the contribution of these cytokines to the gut mucosal barrier during bacterial infection.
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Affiliation(s)
- Maria Valeri
- Department of Microbiology and Molecular Genetics, University of California Irvine School of Medicine, Irvine, CA 92697-4025, USA
- Institute for Immunology, University of California Irvine School of Medicine, Irvine, CA 92697-4025, USA
| | - Manuela Raffatellu
- Department of Microbiology and Molecular Genetics, University of California Irvine School of Medicine, Irvine, CA 92697-4025, USA
- Institute for Immunology, University of California Irvine School of Medicine, Irvine, CA 92697-4025, USA
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30
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Genetic variant of IL-10RA and susceptibility to rheumatoid arthritis in a Chinese population. Clin Rheumatol 2016; 36:825-830. [DOI: 10.1007/s10067-016-3449-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Revised: 09/04/2016] [Accepted: 10/06/2016] [Indexed: 11/26/2022]
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31
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Galien R. Janus kinases in inflammatory bowel disease: Four kinases for multiple purposes. Pharmacol Rep 2016; 68:789-96. [DOI: 10.1016/j.pharep.2016.04.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2016] [Revised: 04/07/2016] [Accepted: 04/11/2016] [Indexed: 02/09/2023]
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32
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Martin JC, Bériou G, Heslan M, Bossard C, Jarry A, Abidi A, Hulin P, Ménoret S, Thinard R, Anegon I, Jacqueline C, Lardeux B, Halary F, Renauld JC, Bourreille A, Josien R. IL-22BP is produced by eosinophils in human gut and blocks IL-22 protective actions during colitis. Mucosal Immunol 2016; 9:539-49. [PMID: 26329427 DOI: 10.1038/mi.2015.83] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2015] [Accepted: 07/31/2015] [Indexed: 02/06/2023]
Abstract
Crohn's disease and ulcerative colitis, the two major forms of inflammatory bowel diseases (IBDs), are characterized by high levels of IL-22 production. Rodent studies revealed that this cytokine is protective during colitis but whether this is true in IBDs is unclear. We show here that levels of the soluble inhibitor of IL-22, interleukin 22-binding protein (IL-22BP), are significantly enhanced during IBDs owing to increased numbers of IL-22BP-producing eosinophils, that we unexpectedly identify as the most abundant source of IL-22BP protein in human gut. In addition, using IL-22BP-deficient rats, we confirm that endogenous IL-22BP is effective at blocking protective actions of IL-22 during acute colitis. In conclusion, our study provides new important insights regarding the biology of IL-22 and IL-22BP in the gut and indicates that protective actions of IL-22 are likely to be suboptimal in IBDs thus making IL-22BP a new relevant therapeutic target.
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Affiliation(s)
- J C Martin
- INSERM Center for Research in Transplantation and Immunology, UMR1064, ITUN, Nantes, France
- Université de Nantes, Faculté de Médecine, Nantes, France
- CHU Nantes, Laboratoire d'Immunologie, Nantes, France
| | - G Bériou
- INSERM Center for Research in Transplantation and Immunology, UMR1064, ITUN, Nantes, France
| | - M Heslan
- INSERM Center for Research in Transplantation and Immunology, UMR1064, ITUN, Nantes, France
| | - C Bossard
- Université de Nantes, Faculté de Médecine, Nantes, France
- EA4273 Biometadys, Faculté de Médecine, Université de Nantes, Nantes, France
- CHU Nantes, Laboratoire d'anatomopathologie, Nantes, France
| | - A Jarry
- EA4273 Biometadys, Faculté de Médecine, Université de Nantes, Nantes, France
| | - A Abidi
- INSERM Center for Research in Transplantation and Immunology, UMR1064, ITUN, Nantes, France
| | - P Hulin
- Plateforme MicroPICell, SFR santé, Nantes, France
| | - S Ménoret
- INSERM Center for Research in Transplantation and Immunology, UMR1064, ITUN, Nantes, France
| | - R Thinard
- INSERM Center for Research in Transplantation and Immunology, UMR1064, ITUN, Nantes, France
| | - I Anegon
- INSERM Center for Research in Transplantation and Immunology, UMR1064, ITUN, Nantes, France
| | - C Jacqueline
- EA3826, Faculté de Médecine, Université de Nantes, Nantes, France
| | - B Lardeux
- Institut des Maladies de l'Appareil Digestif - IMAD, INSERM UMR913, Nantes, France
| | - F Halary
- INSERM Center for Research in Transplantation and Immunology, UMR1064, ITUN, Nantes, France
| | - J-C Renauld
- Ludwig Institute for Cancer Research, Brussels, Belgium
- Institut de Duve, Université catholique de Louvain, Brussels, Belgium
| | - A Bourreille
- Institut des Maladies de l'Appareil Digestif - IMAD, INSERM UMR913, Nantes, France
- Institut des Maladies de l'Appareil Digestif - IMAD, INSERM CIC-04, CHU Nantes, Nantes, France
| | - R Josien
- INSERM Center for Research in Transplantation and Immunology, UMR1064, ITUN, Nantes, France
- Université de Nantes, Faculté de Médecine, Nantes, France
- CHU Nantes, Laboratoire d'Immunologie, Nantes, France
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Wilbers RHP, Westerhof LB, Reuter LJ, Castilho A, van Raaij DR, Nguyen DL, Lozano-Torres JL, Smant G, Hokke CH, Bakker J, Schots A. The N-glycan on Asn54 affects the atypical N-glycan composition of plant-produced interleukin-22, but does not influence its activity. PLANT BIOTECHNOLOGY JOURNAL 2016; 14:670-81. [PMID: 26059044 PMCID: PMC11389127 DOI: 10.1111/pbi.12414] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Revised: 04/14/2015] [Accepted: 05/03/2015] [Indexed: 05/27/2023]
Abstract
Human interleukin-22 (IL-22) is a member of the IL-10 cytokine family that has recently been shown to have major therapeutic potential. IL-22 is an unusual cytokine as it does not act directly on immune cells. Instead, IL-22 controls the differentiation, proliferation and antimicrobial protein expression of epithelial cells, thereby maintaining epithelial barrier function. In this study, we transiently expressed human IL-22 in Nicotiana benthamiana plants and investigated the role of N-glycosylation on protein folding and biological activity. Expression levels of IL-22 were up to 5.4 μg/mg TSP, and N-glycan analysis revealed the presence of the atypical Lewis A structure. Surprisingly, upon engineering of human-like N-glycans on IL-22 by co-expressing mouse FUT8 in ΔXT/FT plants a strong reduction in Lewis A was observed. Also, core α1,6-fucoylation did not improve the biological activity of IL-22. The combination of site-directed mutagenesis of Asn54 and in vivo deglycosylation with PNGase F also revealed that N-glycosylation at this position is not required for proper protein folding. However, we do show that the presence of a N-glycan on Asn54 contributes to the atypical N-glycan composition of plant-produced IL-22 and influences the N-glycan composition of N-glycans on other positions. Altogether, our data demonstrate that plants offer an excellent tool to investigate the role of N-glycosylation on folding and activity of recombinant glycoproteins, such as IL-22.
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Affiliation(s)
- Ruud H P Wilbers
- Plant Sciences Department, Laboratory of Nematology, Wageningen University and Research Centre, Wageningen, The Netherlands
| | - Lotte B Westerhof
- Plant Sciences Department, Laboratory of Nematology, Wageningen University and Research Centre, Wageningen, The Netherlands
| | - Lauri J Reuter
- VTT Technical Research Centre of Finland, Espoo, Finland
| | - Alexandra Castilho
- Department of Applied Genetics and Cell Biology, University of Natural Resources and Life Sciences, Vienna, Austria
| | - Debbie R van Raaij
- Plant Sciences Department, Laboratory of Nematology, Wageningen University and Research Centre, Wageningen, The Netherlands
| | - Dieu-Linh Nguyen
- Department of Parasitology, Parasite Glycobiology Group, Leiden University Medical Center, Leiden, The Netherlands
| | - Jose L Lozano-Torres
- Plant Sciences Department, Laboratory of Nematology, Wageningen University and Research Centre, Wageningen, The Netherlands
| | - Geert Smant
- Plant Sciences Department, Laboratory of Nematology, Wageningen University and Research Centre, Wageningen, The Netherlands
| | - Cornelis H Hokke
- Department of Parasitology, Parasite Glycobiology Group, Leiden University Medical Center, Leiden, The Netherlands
| | - Jaap Bakker
- Plant Sciences Department, Laboratory of Nematology, Wageningen University and Research Centre, Wageningen, The Netherlands
| | - Arjen Schots
- Plant Sciences Department, Laboratory of Nematology, Wageningen University and Research Centre, Wageningen, The Netherlands
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Parks OB, Pociask DA, Hodzic Z, Kolls JK, Good M. Interleukin-22 Signaling in the Regulation of Intestinal Health and Disease. Front Cell Dev Biol 2016; 3:85. [PMID: 26793707 PMCID: PMC4710696 DOI: 10.3389/fcell.2015.00085] [Citation(s) in RCA: 120] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2015] [Accepted: 12/14/2015] [Indexed: 12/25/2022] Open
Abstract
Interleukin (IL)-22 is a member of the IL-10 family of cytokines that has been extensively studied since its discovery in 2000. This review article aims to describe the cellular sources and signaling pathways of this cytokine as well as the functions of IL-22 in the intestine. In addition, this article describes the roles of IL-22 in the pathogenesis of several gastrointestinal diseases, including inhibition of inflammation and barrier defense against pathogens within the intestine. Since many of the functions of IL-22 in the intestine are incompletely understood, this review is meant to assess our current understanding of the roles of IL-22 and provide new opportunities for inquiry to improve human intestinal health and disease.
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Affiliation(s)
- Olivia B Parks
- Department of Pediatrics, University of Pittsburgh School of Medicine Pittsburgh, PA, USA
| | - Derek A Pociask
- Department of Pediatrics, University of Pittsburgh School of MedicinePittsburgh, PA, USA; Department of Pediatrics, Richard King Mellon Foundation Institute for Pediatric Research, University of Pittsburgh School of MedicinePittsburgh, PA, USA
| | - Zerina Hodzic
- Department of Pediatrics, University of Pittsburgh School of Medicine Pittsburgh, PA, USA
| | - Jay K Kolls
- Department of Pediatrics, University of Pittsburgh School of MedicinePittsburgh, PA, USA; Department of Pediatrics, Richard King Mellon Foundation Institute for Pediatric Research, University of Pittsburgh School of MedicinePittsburgh, PA, USA
| | - Misty Good
- Department of Pediatrics, University of Pittsburgh School of MedicinePittsburgh, PA, USA; Division of Newborn Medicine, Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh School of MedicinePittsburgh, PA, USA
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Wawrzyniak M, Ochsner U, Wirz O, Wawrzyniak P, van de Veen W, Akdis CA, Akdis M. A novel, dual cytokine-secretion assay for the purification of human Th22 cells that do not co-produce IL-17A. Allergy 2016; 71:47-57. [PMID: 26392196 DOI: 10.1111/all.12768] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/14/2015] [Indexed: 12/21/2022]
Abstract
BACKGROUND Interleukin-22 is produced by certain T helper cells subsets (Th17, Th22) and at lower levels by γ-δ T cells, NKT and innate lymphoid cells. Th22 cells are unique immune cells that regulate tissue responses by IL-22 production. The exact discrimination between Th17 cells that co-produce IL-22 and single IL-22-producing Th22 cells has not been possible until the present study. Isolation of pure Th22 cells without co-expression of cytokines of other T-cell subsets is essential to better understand their function in humans. The aim of this study is the isolation and characterization of viable, human IL-22-producing CD4+ T cells that do not produce IL-17A. METHODS Isolation of viable Th22 cells was performed with the combination of two cytokine secretion assays detecting IL-17A- and IL-22-producing cells in a single purification step. RESULTS The newly developed cytokine secretion assay consists of anti-IL-22 and anti-IL-17A catch antibodies, which via biotin-streptavidin interaction are bound to the biotinylated surface of the target cell, and anti-IL-22 and IL-17A detection antibody labelled with a fluorescent dye, which detects cytokines bound to these catch antibodies. A unique population of human Th22 cells, which do not produce IL-17A, was sorted, and cytokine expression pattern was confirmed by quantitative PCR analysis and ELISA. The presented technique allows the detection and isolation of pure human Th22 cells. CONCLUSIONS This technique may allow the purification of any single cytokine-producing cell subset, and the combination of several different cytokine secretion assays can be used to purify and characterize novel and unique cell subsets.
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Affiliation(s)
- M Wawrzyniak
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
| | - U Ochsner
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
| | - O Wirz
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
| | - P Wawrzyniak
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
- CK-CARE AG - Christine Kühne - Center for Allergy Research and Education, Davos, Switzerland
| | - W van de Veen
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
| | - C A Akdis
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
- CK-CARE AG - Christine Kühne - Center for Allergy Research and Education, Davos, Switzerland
| | - M Akdis
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
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36
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Morrison PJ, Ballantyne SJ, Macdonald SJ, Moore JWJ, Jenkins D, Wright JF, Fouser LA, Kullberg MC. Differential Requirements for IL-17A and IL-22 in Cecal versus Colonic Inflammation Induced by Helicobacter hepaticus. THE AMERICAN JOURNAL OF PATHOLOGY 2015; 185:3290-303. [PMID: 26458765 PMCID: PMC4729236 DOI: 10.1016/j.ajpath.2015.08.015] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/07/2015] [Revised: 07/24/2015] [Accepted: 08/06/2015] [Indexed: 12/19/2022]
Abstract
Type 17 helper T-cell cytokines have been implicated in the pathogenesis of inflammatory bowel disease, a chronic condition affecting the gastrointestinal tract, but information regarding their contribution to pathology in different regions of the gut is lacking. By using a murine model of bacteria-induced typhlocolitis, we investigated the role of IL-17A, IL-17F, and IL-22 in cecal versus colonic inflammation. Cecal, but not colonic, pathology in C57BL/6 mice inoculated with Helicobacter hepaticus plus anti-IL-10 receptor (IL-10R) monoclonal antibody was exacerbated by co-administration of anti-IL-17A monoclonal antibody, suggesting a disease-protective role for IL-17A in the cecum. In contrast, anti-IL-17F had no effect on H. hepaticus-induced intestinal pathology. Neutralization of IL-22 prevented the development of colonic, but not cecal, inflammation in H. hepaticus-infected anti-IL-10R-treated mice, demonstrating a pathogenic role for IL-22 in the colon. Analysis of transcript levels revealed differential expression of IL-22R, IL-22 binding protein, and IL-23R between cecum and colon, a finding that may help explain why these tissues respond differently after anti-IL-22 treatment. Analysis of microarray data from healthy human intestine further revealed significant differences in cytokine receptor transcript levels (including IL-22RA1 and IL-23R) in distinct parts of the human gut. Together, our findings demonstrate that individual type 17 helper T-cell cytokines can have proinflammatory or anti-inflammatory effects in different regions of the intestine, an observation that may have implications for interventions against human inflammatory bowel disease.
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Affiliation(s)
- Peter J Morrison
- Centre for Immunology and Infection, Department of Biology and Hull York Medical School, University of York, York, United Kingdom
| | - Sarah J Ballantyne
- Centre for Immunology and Infection, Department of Biology and Hull York Medical School, University of York, York, United Kingdom
| | - Sandy J Macdonald
- Centre for Chronic Diseases and Disorders, Department of Biology, University of York, York, United Kingdom
| | - John W J Moore
- Centre for Immunology and Infection, Department of Biology and Hull York Medical School, University of York, York, United Kingdom
| | - David Jenkins
- Centre for Immunology and Infection, Department of Biology and Hull York Medical School, University of York, York, United Kingdom
| | - Jill F Wright
- Development Operations, Pfizer Biotherapeutics Research and Development, Cambridge, Massachusetts
| | - Lynette A Fouser
- Development Operations, Pfizer Biotherapeutics Research and Development, Cambridge, Massachusetts
| | - Marika C Kullberg
- Centre for Immunology and Infection, Department of Biology and Hull York Medical School, University of York, York, United Kingdom.
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Physiological and Pathological Properties of Interleukin-22 in Liver Diseases. CURRENT PATHOBIOLOGY REPORTS 2015. [DOI: 10.1007/s40139-015-0088-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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38
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Cen Y, Guo XY, Jiang HX. Interleukin-22 activates JAK-STAT3 pathway: Role in liver disease. Shijie Huaren Xiaohua Zazhi 2015; 23:2228-2233. [DOI: 10.11569/wcjd.v23.i14.2228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Interleukin (IL)-22 belongs to the IL-10 family and is secreted mainly by Th22 cells. IL-22 binds to IL-22 receptors which are expressed in special tissues and cells, and activates the signal transducer and activator of transcription 3 (STAT3) signal pathway. IL-22 has a role in liver injury primarily through activating the STAT3 signal pathway. In different types of liver injury, IL-22 protects the liver or aggravates liver injury. This paper will review the role of IL-22 in liver disease in terms of activating the STAT3 signal pathway.
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Abstract
Interleukin-22 (IL-22) is a recently described IL-10 family cytokine that is produced by T helper (Th) 17 cells, γδ T cells, NKT cells, and newly described innate lymphoid cells (ILCs). Knowledge of IL-22 biology has evolved rapidly since its discovery in 2000, and a role for IL-22 has been identified in numerous tissues, including the intestines, lung, liver, kidney, thymus, pancreas, and skin. IL-22 primarily targets nonhematopoietic epithelial and stromal cells, where it can promote proliferation and play a role in tissue regeneration. In addition, IL-22 regulates host defense at barrier surfaces. However, IL-22 has also been linked to several conditions involving inflammatory tissue pathology. In this review, we assess the current understanding of this cytokine, including its physiologic and pathologic effects on epithelial cell function.
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Zdrenghea MT, Makrinioti H, Muresan A, Johnston SL, Stanciu LA. The role of macrophage IL-10/innate IFN interplay during virus-induced asthma. Rev Med Virol 2014; 25:33-49. [PMID: 25430775 PMCID: PMC4316183 DOI: 10.1002/rmv.1817] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2014] [Revised: 08/25/2014] [Accepted: 10/14/2014] [Indexed: 12/18/2022]
Abstract
Activation through different signaling pathways results in two functionally different types of macrophages, the pro-inflammatory (M1) and the anti-inflammatory (M2). The polarization of macrophages toward the pro-inflammatory M1 phenotype is considered to be critical for efficient antiviral immune responses in the lung. Among the various cell types that are present in the asthmatic airways, macrophages have emerged as significant participants in disease pathogenesis, because of their activation during both the inflammatory and resolution phases, with an impact on disease progression. Polarized M1 and M2 macrophages are able to reversibly undergo functional redifferentiation into anti-inflammatory or pro-inflammatory macrophages, respectively, and therefore, macrophages mediate both processes. Recent studies have indicated a predominance of M2 macrophages in asthmatic airways. During a virus infection, it is likely that M2 macrophages would secrete higher amounts of the suppressor cytokine IL-10, and less innate IFNs. However, the interactions between IL-10 and innate IFNs during virus-induced exacerbations of asthma have not been well studied. The possible role of IL-10 as a therapy in allergic asthma has already been suggested, but the divergent roles of this suppressor molecule in the antiviral immune response raise concerns. This review attempts to shed light on macrophage IL-10-IFNs interactions and discusses the role of IL-10 in virus-induced asthma exacerbations. Whereas IL-10 is important in terminating pro-inflammatory and antiviral immune responses, the presence of this immune regulatory cytokine at the beginning of virus infection could impair the response to viruses and play a role in virus-induced asthma exacerbations.
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Affiliation(s)
- Mihnea T Zdrenghea
- Ion Chiricuta Oncology InstituteCluj-Napoca, Romania
- Iuliu Hatieganu, University of Medicine and PharmacyCluj-Napoca, Romania
| | - Heidi Makrinioti
- Airways Disease Infection Section, National Heart and Lung Institute, Imperial College LondonLondon, UK
- Medical Research Council and Asthma UK Centre in Allergic Mechanisms of AsthmaLondon, UK
- Centre for Respiratory InfectionsLondon, UK
| | - Adriana Muresan
- Iuliu Hatieganu, University of Medicine and PharmacyCluj-Napoca, Romania
| | - Sebastian L Johnston
- Airways Disease Infection Section, National Heart and Lung Institute, Imperial College LondonLondon, UK
- Medical Research Council and Asthma UK Centre in Allergic Mechanisms of AsthmaLondon, UK
- Centre for Respiratory InfectionsLondon, UK
| | - Luminita A Stanciu
- Iuliu Hatieganu, University of Medicine and PharmacyCluj-Napoca, Romania
- Airways Disease Infection Section, National Heart and Lung Institute, Imperial College LondonLondon, UK
- Medical Research Council and Asthma UK Centre in Allergic Mechanisms of AsthmaLondon, UK
- Centre for Respiratory InfectionsLondon, UK
- *
Correspondence to: Dr. L. A. Stanciu, MD, PhD, Airway Disease Infection Section, Imperial College London, London, UK., E-mail:
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Williams JA, Manley S, Ding WX. New advances in molecular mechanisms and emerging therapeutic targets in alcoholic liver diseases. World J Gastroenterol 2014; 20:12908-12933. [PMID: 25278688 PMCID: PMC4177473 DOI: 10.3748/wjg.v20.i36.12908] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2013] [Revised: 03/07/2014] [Accepted: 04/16/2014] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver disease is a major health problem in the United States and worldwide. Chronic alcohol consumption can cause steatosis, inflammation, fibrosis, cirrhosis and even liver cancer. Significant progress has been made to understand key events and molecular players for the onset and progression of alcoholic liver disease from both experimental and clinical alcohol studies. No successful treatments are currently available for treating alcoholic liver disease; therefore, development of novel pathophysiological-targeted therapies is urgently needed. This review summarizes the recent progress on animal models used to study alcoholic liver disease and the detrimental factors that contribute to alcoholic liver disease pathogenesis including miRNAs, S-adenosylmethionine, Zinc deficiency, cytosolic lipin-1β, IRF3-mediated apoptosis, RIP3-mediated necrosis and hepcidin. In addition, we summarize emerging adaptive protective effects induced by alcohol to attenuate alcohol-induced liver pathogenesis including FoxO3, IL-22, autophagy and nuclear lipin-1α.
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Wang X, Ouyang W. Interleukin-22: A Bridge Between Epithelial Innate Host Defense and Immune Cells. CYTOKINE FRONTIERS 2014. [PMCID: PMC7120444 DOI: 10.1007/978-4-431-54442-5_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Interleukin-22 (IL-22), an IL-10 family cytokine, is produced by various leukocytes. The receptor of IL-22, however, is preferentially detected on peripheral tissue epithelial cells. IL-22 functions as a unique messenger from immune system to tissue epithelial cells and to regulate homeostasis of epithelia. IL-22 is able to directly enhance antimicrobial defense mechanisms in epithelial cells and to facilitate epithelial barrier repair and wound healing process. It, therefore, possesses an irreplaceable role in host defense against certain pathogens that specifically invade epithelial cells. In addition, IL-22 can help to preserve the integrity and homeostasis of various epithelial organs during infection or inflammation. The importance of its tissue-protective function is manifested in many inflammatory situations such as inflammatory bowel diseases (IBD) and hepatitis. On the other hand, as a cytokine, IL-22 is capable of induction of proinflammatory responses, especially in synergy with other cytokines. Consequently, IL-22 contributes to pathogenesis of certain inflammatory diseases for example psoriasis.
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Abstract
Interleukin-22 (IL-22) is a key effector molecule that is produced by activated T cells, including T helper 22 (TH22) cells, TH17 cells and TH1 cells, as well as subsets of innate lymphoid cells. Although IL-22 can act synergistically with IL-17 or tumour necrosis factor, some important functions of IL-22 are unique to this cytokine. Data obtained over the past few years indicate that the IL-22-IL-22 receptor subunit 1 (IL-22R1) system has a high potential clinical relevance in psoriasis, ulcerative colitis, graft-versus-host disease, certain infections and tumours, as well as in liver and pancreas damage. This Review highlights current knowledge of the biology of the IL-22-IL-22R1 system, its role in inflammation, tissue protection, regeneration and antimicrobial defence, as well as the positive and potentially negative consequences of its therapeutic modulation.
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Affiliation(s)
- Robert Sabat
- 1] Interdisciplinary Group of Molecular Immunopathology, Institute of Medical Immunology, Department of Dermatology and Allergy, University Medicine Charité, Charitéplatz 1, D-10117 Berlin, Germany. [2] Research Center Immunosciences, University Hospital Charité, Hessische Strasse 3-4, D-10115 Berlin, Germany
| | - Wenjun Ouyang
- Department of Immunology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA
| | - Kerstin Wolk
- 1] Interdisciplinary Group of Molecular Immunopathology, Institute of Medical Immunology, Department of Dermatology and Allergy, University Medicine Charité, Charitéplatz 1, D-10117 Berlin, Germany. [2] Research Center Immunosciences, University Hospital Charité, Hessische Strasse 3-4, D-10115 Berlin, Germany
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Martin JCJ, Bériou G, Heslan M, Chauvin C, Utriainen L, Aumeunier A, Scott CL, Mowat A, Cerovic V, Houston SA, Leboeuf M, Hubert FX, Hémont C, Merad M, Milling S, Josien R. Interleukin-22 binding protein (IL-22BP) is constitutively expressed by a subset of conventional dendritic cells and is strongly induced by retinoic acid. Mucosal Immunol 2014; 7:101-13. [PMID: 23653115 PMCID: PMC4291114 DOI: 10.1038/mi.2013.28] [Citation(s) in RCA: 118] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2012] [Accepted: 04/08/2013] [Indexed: 02/04/2023]
Abstract
Interleukin-22 (IL-22) is mainly produced at barrier surfaces by T cells and innate lymphoid cells and is crucial to maintain epithelial integrity. However, dysregulated IL-22 action leads to deleterious inflammation and is involved in diseases such as psoriasis, intestinal inflammation, and cancer. IL-22 binding protein (IL-22BP) is a soluble inhibitory IL-22 receptor and may represent a crucial regulator of IL-22. We show both in rats and mice that, in the steady state, the main source of IL-22BP is constituted by a subset of conventional dendritic cells (DCs) in lymphoid and non-lymphoid tissues. In mouse intestine, IL-22BP was specifically expressed in lamina propria CD103(+)CD11b(+) DC. In humans, IL-22BP was expressed in immature monocyte-derived DC and strongly induced by retinoic acid but dramatically reduced upon maturation. Our data suggest that a subset of immature DCs may actively participate in the regulation of IL-22 activity in the gut by producing high levels of IL-22BP.
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Affiliation(s)
- JCJ Martin
- INSERM Center of Research in Transplantation and Immunology, UMR1064, Nantes, F - 44000, France,CHU Nantes, Institut de Transplantation Urologie Néphrologie (ITUN), Nantes, F-44000, France,CHU Nantes, Laboratoire d’immunologie, Nantes, F-44000, France,Université de Nantes, Faculté de Médecine, Nantes, F-44000, France
| | - G Bériou
- INSERM Center of Research in Transplantation and Immunology, UMR1064, Nantes, F - 44000, France,CHU Nantes, Institut de Transplantation Urologie Néphrologie (ITUN), Nantes, F-44000, France
| | - M Heslan
- INSERM Center of Research in Transplantation and Immunology, UMR1064, Nantes, F - 44000, France,CHU Nantes, Institut de Transplantation Urologie Néphrologie (ITUN), Nantes, F-44000, France
| | - C Chauvin
- INSERM Center of Research in Transplantation and Immunology, UMR1064, Nantes, F - 44000, France,CHU Nantes, Institut de Transplantation Urologie Néphrologie (ITUN), Nantes, F-44000, France
| | - L Utriainen
- Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8TA, UK
| | - A Aumeunier
- Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8TA, UK
| | - CL Scott
- Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8TA, UK
| | - A Mowat
- Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8TA, UK
| | - V Cerovic
- Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8TA, UK
| | - SA Houston
- Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8TA, UK
| | - M Leboeuf
- Department of Gene and Cell medicine and the Department of Medicine, Mount Sinai School of Medicine, New York 10029, USA
| | - FX Hubert
- INSERM Center of Research in Transplantation and Immunology, UMR1064, Nantes, F - 44000, France,CHU Nantes, Institut de Transplantation Urologie Néphrologie (ITUN), Nantes, F-44000, France,Université de Nantes, Faculté de Médecine, Nantes, F-44000, France
| | - C Hémont
- INSERM Center of Research in Transplantation and Immunology, UMR1064, Nantes, F - 44000, France,CHU Nantes, Institut de Transplantation Urologie Néphrologie (ITUN), Nantes, F-44000, France,CHU Nantes, Laboratoire d’immunologie, Nantes, F-44000, France,Université de Nantes, Faculté de Médecine, Nantes, F-44000, France
| | - M Merad
- Department of Gene and Cell medicine and the Department of Medicine, Mount Sinai School of Medicine, New York 10029, USA
| | - S Milling
- Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8TA, UK
| | - R Josien
- INSERM Center of Research in Transplantation and Immunology, UMR1064, Nantes, F - 44000, France,CHU Nantes, Institut de Transplantation Urologie Néphrologie (ITUN), Nantes, F-44000, France,CHU Nantes, Laboratoire d’immunologie, Nantes, F-44000, France,Université de Nantes, Faculté de Médecine, Nantes, F-44000, France
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Jia L, Wu C. The biology and functions of Th22 cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2014; 841:209-30. [PMID: 25261209 DOI: 10.1007/978-94-017-9487-9_8] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
T helper (Th) cells develop from naïve CD4(+) T cells under lineage-specific culture conditions and are nominated by their lineage-specific cytokines. Th22 cells, new players in adoptive immune responses, are identified by the production of interleukin (IL)-22. Plenty of observations are obtained over the past few years indicating that IL-22 is produced by activated T cells including Th22 cells, Th17 cells, Th1 cells, innate lymphoid cells and some nonlymphocytes. IL-22 functions synergistically with IL-17 or tumor necrosis factor (TNF), however, it plays different roles by IL-22/IL-22 receptor signal transductions in pathologic processes, including inflammations, autoimmunity, tumor, and digestive organs damages. In this chapter, we focus on the biology of IL-22, the generation and regulation of Th22 cells, the possible signal pathways that involved in the functions of Th22 cells, as well as the relationship between Th22 cells and various diseases.
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Affiliation(s)
- Lei Jia
- Key Laboratory of Tropical Disease Control Research of Ministry of Education, Zhongshan School of Medicine, Institute of Immunology, Sun Yat-Sen University, 74th, Zhongshan 2nd Road, Guangzhou, 510080, China
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The molecular basis of IL-10 function: from receptor structure to the onset of signaling. Curr Top Microbiol Immunol 2014; 380:191-212. [PMID: 25004819 DOI: 10.1007/978-3-662-43492-5_9] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Assembly of the cell surface IL-10 receptor complex is the first step in initiating IL-10 signaling pathways that regulate intestinal inflammation, viral persistence and even tumor surveillance. The discovery of IL-10 homologs in the genomes of herpes viruses suggests IL-10 signaling pathways can be manipulated at the level of the receptor complex. This chapter will describe our current molecular understanding of IL-10 receptor assembly based on crystal structures and biochemical analyses of cellular and viral IL-10 receptor complexes.
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Peng H, Wang W, Zhou M, Li R, Pan HF, Ye DQ. Role of interleukin-10 and interleukin-10 receptor in systemic lupus erythematosus. Clin Rheumatol 2013; 32:1255-66. [PMID: 23708831 DOI: 10.1007/s10067-013-2294-3] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2013] [Accepted: 05/13/2013] [Indexed: 01/22/2023]
Abstract
Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by excessive production of a variety of autoantibodies, accumulation of immune complexes, and multiple organ systems involvement. Interleukin-10 (IL-10) has an important role in the growth, survival, differentiation, and function of B cells. Abnormally increased IL-10 synthesis seems contributing to the spontaneous hyperactivity of the B cell compartment, so that it can directly result in autoantibody production by committed plasma cells, circulating immune complexes formation, and eventually in tissue and organ damage, suggesting it might associate with the development of SLE. A better understanding of the regulation of IL-10 and its receptors (IL-10R) can likely provide more valuable clues to the pathogenic mechanisms underlying specific forms of SLE, so as to pave the way toward more effective therapeutics.
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Affiliation(s)
- Hui Peng
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, 230032, People's Republic of China
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Niv-Spector L, Shpilman M, Levi-Bober M, Katz M, Varol C, Elinav E, Gertler A. Preparation and characterization of mouse IL-22 and its four single-amino-acid muteins that act as IL-22 receptor-1 antagonists. Protein Eng Des Sel 2012; 25:397-404. [PMID: 22691704 DOI: 10.1093/protein/gzs030] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Recombinant mouse interleukin 22 (mIL-22) and its variants encoding four muteins (Y51A, N54A, R55A and E117A) were expressed in Escherichia coli, refolded and purified to homogeneity as monomeric proteins by one-step ion-exchange chromatography. The binding of IL-22 and its four muteins to immobilized mIL-22 receptor α1 extracellular domain (mIL-22 Rα1-ECD) exhibited similar affinity, indicating that the single-amino-acid mutations do not affect its binding properties. Similarly, no differences were found in binding to IL-22 binding protein expressed on the surface of yeast cells, although the affinity of all five proteins to the binding protein was higher than that to IL-22 Rα1-ECD. In an in vitro bioassay, recombinant mIL-22 stimulated signal transducer and activator of transcription-3 phosphorylation in HepG2 cells, whereas the four muteins were completely (Y51A) or almost completely (N54A, R55A and E117A) devoid of this agonistic activity. Furthermore, the agonistic activity of mIL-22 could be inhibited in a dose-dependent manner by the four muteins with almost identical efficiency. mIL-22 and its Y51A mutein were pegylated by methoxy polyethylene glycol-propionylaldehyde-20 kDa, yielding a mixture of mono (75-80%) and double (20-25%) pegylated proteins. The pegylated proteins showed lower affinity (50 and 25%) toward immobilized mIL-22 Rα1-ECD than their non-pegylated analogs. Wild-type pegylated IL-22 exhibited 5- to 10-fold lower activity in the HepG2 bioassay than its non-pegylated counterpart. Preparation of recombinant mIL-22 antagonists provides new tools for the study of IL-22 activity and of eventual therapeutic means for attenuating its negative effects.
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Affiliation(s)
- Leonora Niv-Spector
- The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University, Rehovot 76100, Israel
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49
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Yoon SI, Jones BC, Logsdon NJ, Harris BD, Kuruganti S, Walter MR. Epstein-Barr virus IL-10 engages IL-10R1 by a two-step mechanism leading to altered signaling properties. J Biol Chem 2012; 287:26586-95. [PMID: 22692218 DOI: 10.1074/jbc.m112.376707] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Human interleukin-10 (hIL-10) is a pleiotropic cytokine that is able to suppress or activate cellular immune responses to protect the host from invading pathogens. Epstein-Barr virus (EBV) encodes a viral IL-10 (ebvIL-10) in its genome that has retained the immunosuppressive activities of hIL-10 but lost the ability to induce immunostimulatory activities on some cells. These functional differences are at least partially due to the ∼1000-fold difference in hIL-10 and ebvIL-10 binding affinity for the IL-10R1·IL-10R2 cell surface receptors. Despite weaker binding to IL-10R1, ebvIL-10 is more active than hIL-10 in inducing B-cell proliferation. To explore this counterintuitive observation further, a series of monomeric and dimeric ebvIL-10·hIL-10 chimeric proteins were produced and characterized for receptor binding and cellular proliferation on TF-1/hIL-10R1 cells that express high levels of the IL-10R1 chain. On this cell line, monomeric chimeras elicited cell proliferation in accordance with how tightly they bound to the IL-10R1 chain. In contrast, dimeric chimeras exhibiting the highest affinity for IL-10R1 exhibited reduced proliferative activity. These distinct activity profiles are correlated with kinetic analyses that reveal that the ebvIL-10 dimer is impaired in its ability to form a 1:2 ebvIL-10·IL-10R1 complex. As a result, the ebvIL-10 dimer functions like a monomer at low IL-10R1 levels, which prevents efficient signaling. At high IL-10R1 levels, the ebvIL-10 dimer is able to induce signaling responses greater than hIL-10. Thus, the ebvIL-10 dimer scaffold is essential to prevent activation of cells with low IL-10R1 levels but to maintain or enhance activity on cells with high IL-10R1 levels.
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Affiliation(s)
- Sung Il Yoon
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA
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50
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Sato T, Terai M, Tamura Y, Alexeev V, Mastrangelo MJ, Selvan SR. Interleukin 10 in the tumor microenvironment: a target for anticancer immunotherapy. Immunol Res 2012; 51:170-82. [PMID: 22139852 DOI: 10.1007/s12026-011-8262-6] [Citation(s) in RCA: 183] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
IL-10 is an immunomodulatory cytokine that is frequently upregulated in various types of cancer. The biological role of IL-10 in cancer is quite complex; however, the presence of IL-10 in advanced metastases and the positive correlation between serum IL-10 levels and progression of disease indicates a critical role of IL-10 in the tumor microenvironment. IL-10 has been shown to directly affect the function of antigen-presenting cells by inhibiting the expression of MHC and costimulatory molecules, which in turn induces immune suppression or tolerance. Additionally, IL-10 downregulates the expression of Th1 cytokines and induces T-regulatory responses. Taken together, a combination of IL-10 antagonism and immunostimulatory treatments such as cancer vaccines, Toll-like receptor agonists, Th1 cytokines, and chemokines would be a logical approach to enhance an antitumor immune response.
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Affiliation(s)
- Takami Sato
- Department of Medical Oncology, Jefferson Medical College of Thomas Jefferson University, 1015 Walnut Street, Suite 1024 Curtis Building, Philadelphia, PA 19107, USA.
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