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Montero-Herradón S, García-Ceca J, Villarejo-Torres M, Zapata AG. Peripheral T-cell responses of EphB2- and EphB3-deficient mice in a model of collagen-induced arthritis. Cell Mol Life Sci 2024; 81:159. [PMID: 38558087 PMCID: PMC10984909 DOI: 10.1007/s00018-024-05197-0] [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: 06/22/2023] [Revised: 12/20/2023] [Accepted: 03/02/2024] [Indexed: 04/04/2024]
Abstract
Both EphB2- and EphB3-deficient mice exhibit profound histological alterations in the thymic epithelial network but few changes in T-cell differentiation, suggesting that this organization would be sufficient to produce functional T lymphocytes. Also, other antigen-presenting cells involved in immunological education could substitute the thymic epithelium. Accordingly, we found an increased frequency of plasmacytoid dendritic cells but not of conventional dendritic cells, medullary fibroblasts or intrathymic B lymphocytes. In addition, there are no lymphoid infiltrates in the organs of mutant mice nor do they contain circulating autoantibodies. Furthermore, attempts to induce arthritic lesions after chicken type II collagen administration fail totally in EphB2-deficient mice whereas all WT and half of the immunized EphB3-/- mice develop a typical collagen-induced arthritis. Our results point out that Th17 cells, IL4-producing Th2 cells and regulatory T cells are key for the induction of disease, but mutant mice appear to have deficits in T cell activation or cell migration properties. EphB2-/- T cells show reduced in vitro proliferative responses to anti-CD3/anti-CD28 antibodies, produce low levels of anti-type II collagen antibodies, and exhibit low proportions of T follicular helper cells. On the contrary, EphB3-/- lymph node cells respond accurately to the different immune stimuli although in lower levels than WT cells but show a significantly reduced migration in in vitro transwell assays, suggesting that no sufficient type II collagen-dependent activated lymphoid cells reached the joints, resulting in reduced arthritic lesions.
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Affiliation(s)
- Sara Montero-Herradón
- Department of Cell Biology, Faculty of Biological Sciences, Complutense University of Madrid, 28040, Madrid, Spain
- Health Research Institute, Hospital 12 de Octubre (imas12), 28041, Madrid, Spain
| | - Javier García-Ceca
- Department of Cell Biology, Faculty of Biological Sciences, Complutense University of Madrid, 28040, Madrid, Spain
- Health Research Institute, Hospital 12 de Octubre (imas12), 28041, Madrid, Spain
| | - Marta Villarejo-Torres
- Department of Cell Biology, Faculty of Biological Sciences, Complutense University of Madrid, 28040, Madrid, Spain
| | - Agustín G Zapata
- Department of Cell Biology, Faculty of Biological Sciences, Complutense University of Madrid, 28040, Madrid, Spain.
- Health Research Institute, Hospital 12 de Octubre (imas12), 28041, Madrid, Spain.
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Iraji D, Oftedal BE, Wolff ASB. Th17 Cells: Orchestrators of Mucosal Inflammation and Potential Therapeutic Targets. Crit Rev Immunol 2023; 43:25-52. [PMID: 37831521 DOI: 10.1615/critrevimmunol.2023050360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2023]
Abstract
T helper 17 (Th17) cells represent a specialized subgroup of effector CD4+ T cells known for their role in provoking neutrophil-driven tissue inflammation, particularly within mucosal tissues. Although they are pivotal for defending the host against extracellular bacteria and fungi, they have also been associated with development of various T cell-mediated inflammatory conditions, autoimmune diseases, and even cancer. Notably, Th17 cells exhibit a dual nature, with different Th17 cell subtypes showcasing distinct effector functions and varying capacities to incite autoimmune tissue inflammation. Furthermore, Th17 cells exhibit significant plasticity, which carries important functional implications, both in terms of their expression of cytokines typically associated with other effector T cell subsets and in their interactions with regulatory CD4+ T cells. The intricate balance of Th17 cytokines can also be a double-edged sword in inflammation, autoimmunity, and cancer. Within this article, we delve into the mechanisms that govern the differentiation, function, and adaptability of Th17 cells. We culminate with an exploration of therapeutic potentials in harnessing the power of Th17 cells and their cytokines. Targeted interventions to modulate Th17 responses are emerging as promising strategies for autoimmunity, inflammation, and cancer treatment. By precisely fine-tuning Th17-related pathways, we may unlock new avenues for personalized therapeutic approaches, aiming to restore immune balance, alleviate the challenges of these disorders, and ultimately enhance the quality of life for individuals affected by them.
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Affiliation(s)
- Dorsa Iraji
- Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Bergithe E Oftedal
- Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Medicine, Haukeland University Hospital, Bergen, Norway
| | - Anette S B Wolff
- Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Medicine, Haukeland University Hospital, Bergen, Norway
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Krutyhołowa A, Strzelec K, Dziedzic A, Bereta GP, Łazarz-Bartyzel K, Potempa J, Gawron K. Host and bacterial factors linking periodontitis and rheumatoid arthritis. Front Immunol 2022; 13:980805. [PMID: 36091038 PMCID: PMC9453162 DOI: 10.3389/fimmu.2022.980805] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 07/27/2022] [Indexed: 02/05/2023] Open
Abstract
Observations from numerous clinical, epidemiological and serological studies link periodontitis with severity and progression of rheumatoid arthritis. The strong association is observed despite totally different aetiology of these two diseases, periodontitis being driven by dysbiotic microbial flora on the tooth surface below the gum line, while rheumatoid arthritis being the autoimmune disease powered by anti-citrullinated protein antibodies (ACPAs). Here we discuss genetic and environmental risk factors underlying development of both diseases with special emphasis on bacteria implicated in pathogenicity of periodontitis. Individual periodontal pathogens and their virulence factors are argued as potentially contributing to putative causative link between periodontal infection and initiation of a chain of events leading to breakdown of immunotolerance and development of ACPAs. In this respect peptidylarginine deiminase, an enzyme unique among prokaryotes for Porphyromonas gingivalis, is elaborated as a potential mechanistic link between this major periodontal pathogen and initiation of rheumatoid arthritis development.
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Affiliation(s)
- Anna Krutyhołowa
- Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
| | - Karolina Strzelec
- Department of Molecular Biology and Genetics, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland
| | - Agata Dziedzic
- Department of Molecular Biology and Genetics, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland
| | - Grzegorz P. Bereta
- Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
| | - Katarzyna Łazarz-Bartyzel
- Department of Periodontology and Oral Medicine, Faculty of Medicine, Medical College, Jagiellonian University, Krakow, Poland
| | - Jan Potempa
- Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland,Department of Oral Immunology and Infectious Diseases, School of Dentistry, University of Louisville, Louisville, KY, United States,*Correspondence: Katarzyna Gawron, ; Jan Potempa,
| | - Katarzyna Gawron
- Department of Molecular Biology and Genetics, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland,*Correspondence: Katarzyna Gawron, ; Jan Potempa,
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Cao J, Ni Y, Zhang H, Ning X, Qi X. Inhibition of Kruppel-like factor 7 attenuates cell proliferation and inflammation of fibroblast-like synoviocytes in rheumatoid arthritis through NF-κB and MAPK signaling pathway. Exp Anim 2022; 71:356-367. [PMID: 35321971 PMCID: PMC9388335 DOI: 10.1538/expanim.21-0200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease, which can lead to joint inflammation and progressive joint destruction. Kruppel-like factor 7 (KLF7) is the member of KLF family and
plays an important role in multiple biological progresses. However, its precise roles in RA have not been described. Present study aimed to investigate the role of KLF7 in RA-fibroblast-like
synoviocytes (FLSs). Data showed that KLF7 expression was obviously upregulated in synovial tissues of rats with adjuvant-induced arthritis. Functional studies demonstrated that the loss of
KLF7 may suppress cell proliferation and the expression of pro-inflammatory factors (IL-6, IL-1β, IL-17A) and matrix metalloproteinase (MMP-1, MMP-3, MMP-13) in FLSs through the inhibition
of phosphorylation of nuclear factor κB (NF-κB) p65 and JNK. We further showed that miR-9a-5p specifically interacts with KLF7 to negatively regulate the expression of KLF7 in RA-FLSs. Taken
together, our results demonstrated that KLF7 which targeted by miR-9a-5p might participate in the pathogenesis of RA by promoting cell proliferation, pro-inflammatory cytokine release and
MMP expression through the activation of NF-κB and JNK pathways in RA-FLSs. Hence, KLF7 could be a novel target for RA therapy.
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Affiliation(s)
- Jingjing Cao
- Teaching and Research Section of Internal Medicine, Hebei Medical University.,Department of Rheumatology and Immunology, Hebei General Hospital
| | - Yanhui Ni
- Department of Cardiology, Hebei General Hospital
| | | | - Xiaoran Ning
- Department of Rheumatology and Immunology, Hebei General Hospital
| | - Xiaoyong Qi
- Teaching and Research Section of Internal Medicine, Hebei Medical University.,Department of Cardiology Center, Hebei General Hospital
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Banerjee S, Nara R, Chakraborty S, Chowdhury D, Haldar S. Integrin Regulated Autoimmune Disorders: Understanding the Role of Mechanical Force in Autoimmunity. Front Cell Dev Biol 2022; 10:852878. [PMID: 35372360 PMCID: PMC8971850 DOI: 10.3389/fcell.2022.852878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 02/08/2022] [Indexed: 11/13/2022] Open
Abstract
The pathophysiology of autoimmune disorders is multifactorial, where immune cell migration, adhesion, and lymphocyte activation play crucial roles in its progression. These immune processes are majorly regulated by adhesion molecules at cell–extracellular matrix (ECM) and cell–cell junctions. Integrin, a transmembrane focal adhesion protein, plays an indispensable role in these immune cell mechanisms. Notably, integrin is regulated by mechanical force and exhibit bidirectional force transmission from both the ECM and cytosol, regulating the immune processes. Recently, integrin mechanosensitivity has been reported in different immune cell processes; however, the underlying mechanics of these integrin-mediated mechanical processes in autoimmunity still remains elusive. In this review, we have discussed how integrin-mediated mechanotransduction could be a linchpin factor in the causation and progression of autoimmune disorders. We have provided an insight into how tissue stiffness exhibits a positive correlation with the autoimmune diseases’ prevalence. This provides a plausible connection between mechanical load and autoimmunity. Overall, gaining insight into the role of mechanical force in diverse immune cell processes and their dysregulation during autoimmune disorders will open a new horizon to understand this physiological anomaly.
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Aloke C, Ibiam UA, Orji OU, Ugwuja EI, Ezeani NN, Aja PM, Obasi NA. Anti-arthritic potential of ethanol and aqueous extracts of stem bark of Cleistopholis patens on complete Freund's adjuvant-induced rheumatoid arthritis in rats. J Ayurveda Integr Med 2019; 12:28-34. [PMID: 31606270 PMCID: PMC8039354 DOI: 10.1016/j.jaim.2018.12.009] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2018] [Revised: 10/31/2018] [Accepted: 12/04/2018] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Traditional medicine intervention has been used in rheumatoid arthritis (RA) treatment due to limitations of conventional drugs. OBJECTIVE This study aimed at evaluating the anti-arthritic potentials of ethanol and aqueous extracts of stem bark of Cleistopholis patens (SBCP) in complete Freund's adjuvant (CFA) induced rheumatoid arthritis in rats. MATERIALS AND METHODS Rheumatoid arthritis was induced in groups 2 to 9 by intradermal injection of 0.1 mlkg-1 chicken type II collagen in CFA into the left hind paw of the rats. Group 1 served as normal control. Group 2 (negative control) received 5 mlkg-1 body weight normal saline while group 3 (positive control) received 10 mg/kg body weight standard drug (indomethacin). Groups 4 to 9 received varied doses of the extracts. After 10 days of RA induction, rats were treated with ethanol and aqueous extracts of SBCP orally at a dose of 400, 600 and 800 mgkg-1 for 21 days. The paw size, body weight changes, inflammatory parameters, lipid peroxidation maker and malondialdehyde (MDA) were assessed. RESULTS Rheumatoid arthritis induction caused marked (p < 0.05) increase in paw size, inflammatory makers and MDA while significant (p < 0.05) reduction was observed in body weight relative to normal control. Treatment with extracts analogous to indomethacin markedly (p < 0.05) decreased the paw size and caused weight gain while the altered inflammatory parameters and MDA were reversed relative to negative control. CONCLUSION The findings suggest that the extracts of SBCP have good antiarthritic potentials comparable to indomethacin and hence could be used in rheumatoid arthritis management.
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Affiliation(s)
- C Aloke
- Department of Medical Biochemistry, Faculty of Basic Medical Sciences, Alex Ekwueme Federal University, Ndufu-Alike, Ikwo, Abakaliki, Ebonyi State, Nigeria.
| | - U A Ibiam
- Department of Biochemistry, Faculty of Sciences, Ebonyi State University, Abakaliki, Nigeria
| | - O U Orji
- Department of Biochemistry, Faculty of Sciences, Ebonyi State University, Abakaliki, Nigeria
| | - E I Ugwuja
- Department of Biochemistry, Faculty of Sciences, Ebonyi State University, Abakaliki, Nigeria
| | - N N Ezeani
- Department of Biochemistry, Faculty of Sciences, Ebonyi State University, Abakaliki, Nigeria
| | - P M Aja
- Department of Biochemistry, Faculty of Sciences, Ebonyi State University, Abakaliki, Nigeria
| | - N A Obasi
- Department of Medical Biochemistry, Faculty of Basic Medical Sciences, Alex Ekwueme Federal University, Ndufu-Alike, Ikwo, Abakaliki, Ebonyi State, Nigeria
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Efficacy and safety of secukinumab in active rheumatoid arthritis with an inadequate response to tumor necrosis factor inhibitors: a meta-analysis of phase III randomized controlled trials. Clin Rheumatol 2019; 38:2765-2776. [PMID: 31087226 DOI: 10.1007/s10067-019-04595-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Revised: 04/21/2019] [Accepted: 05/06/2019] [Indexed: 12/14/2022]
Abstract
OBJECTIVES To address the efficacy and safety of secukinumab in comparison with placebo in active rheumatoid arthritis (RA) patients who had an inadequate response to tumor necrosis factor (TNF) inhibitors. METHODS Databases of PubMed, Embase, and Web of Science were searched to identify the relevant randomized controlled trials (RCTs). Risk ratio (RR) and 95% confidence interval (95% CI) were calculated with the Mantel-Haenszel random effects method. Statistical heterogeneity was assessed using the Cochran Q and I2 tests. RESULTS A total of 1292 patients from three phase III RCT studies were included. Compared with placebo, secukinumab 150 mg was superior at 24 weeks in terms of ACR20 with RR (1.66, 95% CI 1.33, 2.08; P < 0.0001; I2 = 0%), ACR50 (1.88, 95% CI 1.29, 2.72; P = 0.0009; I2 = 0%), and ACR70 (2.15, 95% CI 1.15, 4.02; P = 0.02; I2 = 0%). Consistent effects were also observed in pooled group of 150 mg and 75 mg secukinumab. For secukinumab 75 mg alone, ACR20 response rate was significantly higher compared with placebo (RR 1.62, 95% CI 1.29, 2.03; P < 0.00001; I2 = 0%). Although ACR50 and ACR70 response rates showed a favorable trend to be higher, no statistical difference was observed (RR 1.68, 95% CI 0.99, 2.85, P = 0.05, I2 = 47%; RR 1.81, 95% CI 0.78, 4.21, P = 0.17, I2 = 34%, respectively). Compared with the placebo group, there was no increased risk of adverse effects (AEs) and serious AEs at 16 weeks in the pooled secukinumab group. CONCLUSIONS In active RA patients with an inadequate response to TNF inhibitors, secukinumab may be a therapeutic option. Secukinumab 150 mg showed significantly better clinical efficacy with no increased risk of AEs and serious AEs compared with placebo. TRIAL REGISTRATION Clinical Trials.gov identifier: NCT01770379, NCT01350804, NCT01377012 Key Points • Secukinumab 150 mg showed significantly better clinical efficacy in active RA patients with an inadequate response to TNF inhibitors. • No increased risk of AEs and serious AEs in secukinumab group compared with placebo.
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Kamel KM, Gad AM, Mansour SM, Safar MM, Fawzy HM. Novel Anti-arthritic Mechanisms of Polydatin in Complete Freund's Adjuvant-Induced Arthritis in Rats: Involvement of IL-6, STAT-3, IL-17, and NF-кB. Inflammation 2018; 41:1974-1986. [PMID: 29982962 DOI: 10.1007/s10753-018-0841-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Articular manifestations are the main hall mark for rheumatoid arthritis; inflammation and oxidative stress are involved in its pathogenesis. This study was designed to figure out the possible therapeutic potential of polydatin on experimentally induced arthritis in rats. Polydatin (POLY) was administered (200 mg/kg, p.o.) for 21 days to complete Freund's adjuvant (CFA; 0.1 ml, s.c.)-induced arthritic rats. Meanwhile, methotrexate (MTX; 0.75 mg/kg, i.p.) was given as a reference standard disease-modifying anti-rheumatic drug (DMARD). Both POLY and MTX significantly attenuated articular damage associated with CFA-induced arthritis. This was manifested by reducing levels of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), interleukin-17 (IL-17), and matrix metalloproteinase-3 (MMP-3), paralleled with marked decrease in hind paw and ankle diameters. Moreover, POLY and MTX downregulated gene expressions of receptor activator of nuclear factor kappa-B ligand (RANKL) as well as signal transducer and activator of transcription-3 (STAT3) besides hampering immunohistochemical staining of vascular endothelial growth factor (VEGF) and nuclear factor kappa-B (NF-κB). Furthermore, substantial decline in myeloperoxidase (MPO) activity and malondialdehyde (MDA) level associated with significant rise in reduced glutathione content (GSH) was observed. These findings provide an innovative therapeutic approach of POLY as a natural anti-arthritic drug through modulating IL-6/STAT-3/IL-17/NF-кB cascade. Graphical Abstract ᅟ.
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Affiliation(s)
- Kamel M Kamel
- Pharmacology Department, National Organization for Drug Control and Research, 6 Abou Hazem St., Pyramids Ave., Giza, Egypt.
| | - Amany M Gad
- Pharmacology Department, National Organization for Drug Control and Research, 6 Abou Hazem St., Pyramids Ave., Giza, Egypt
| | - Suzan M Mansour
- Pharmacology & Toxicology Department, Faculty of Pharmacy, Cairo University, Kasr El-Aini St., Cairo, 11562, Egypt
- Pharmacology, Toxicology & Biochemistry Department, Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University in Egypt, End of 90th St., Fifth Settlement, New Cairo, Egypt
| | - Marwa M Safar
- Pharmacology & Toxicology Department, Faculty of Pharmacy, Cairo University, Kasr El-Aini St., Cairo, 11562, Egypt
- Pharmacology & Biochemistry Department, Faculty of Pharmacy, The British University in Egypt, Suez Desert Road, El Sherouk City, Cairo, 11837, Egypt
| | - Hala M Fawzy
- Pharmacology Department, National Organization for Drug Control and Research, 6 Abou Hazem St., Pyramids Ave., Giza, Egypt
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Kamel KM, Gad AM, Mansour SM, Safar MM, Fawzy HM. Novel Anti-arthritic Mechanisms of Polydatin in Complete Freund’s Adjuvant-Induced Arthritis in Rats: Involvement of IL-6, STAT-3, IL-17, and NF-кB. Inflammation 2018. [DOI: https://doi.org/10.1007/s10753-018-0841-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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Ebrahimiyan H, Aslani S, Rezaei N, Jamshidi A, Mahmoudi M. Survivin and autoimmunity; the ins and outs. Immunol Lett 2018; 193:14-24. [DOI: 10.1016/j.imlet.2017.11.004] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2017] [Revised: 09/13/2017] [Accepted: 11/06/2017] [Indexed: 02/06/2023]
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Tahir H, Deodhar A, Genovese M, Takeuchi T, Aelion J, Van den Bosch F, Haemmerle S, Richards HB. Secukinumab in Active Rheumatoid Arthritis after Anti-TNFα Therapy: A Randomized, Double-Blind Placebo-Controlled Phase 3 Study. Rheumatol Ther 2017; 4:475-488. [PMID: 29138986 PMCID: PMC5696298 DOI: 10.1007/s40744-017-0086-y] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Indexed: 12/14/2022] Open
Abstract
Introduction ‘REASSURE’ (NCT01377012), a phase 3 study, evaluated the efficacy and safety of secukinumab in patients with active rheumatoid arthritis (RA) who had an inadequate response to, or intolerance of, tumor necrosis factor inhibitors (TNF-inhibitors). Methods A total of 637 patients were randomized (1:1:1) to receive intravenous secukinumab 10 mg/kg (baseline, weeks 2 and 4) followed by subcutaneous secukinumab 150 mg or 75 mg every 4 weeks (starting from week 8) or placebo at the same dosing schedule. The primary endpoint was the American College of Rheumatology 20% improvement criteria (ACR20) at week 24. Other predefined hierarchical endpoints included Health Assessment Questionnaire-Disability Index, van der Heijde modified total Sharp score (vdH-mTSS) at week 24, and major clinical response (MCR; continuous 6 month period of ACR70 response) at 1 year. Results The primary efficacy endpoint was met with both secukinumab dose groups: ACR20 response rate at week 24 was 35.2% for both secukinumab dose groups (P = 0.0009) vs 19.6% for placebo. The improvements in secondary endpoints were greater in the secukinumab dose groups vs placebo but did not meet statistical significance. The overall safety profile was similar across all treatment groups. Conclusion Secukinumab demonstrated efficacy in reducing disease activity over placebo as measured by ACR20 in patients with active RA who had an inadequate response to TNF-inhibitors. Secukinumab demonstrated a safety profile similar to other biologics currently approved for RA. Funding Novartis Pharma AG. Trial registration ClinicalTrials.gov identifier: NCT01377012. Electronic supplementary material The online version of this article (doi:10.1007/s40744-017-0086-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
| | - Atul Deodhar
- Oregon Health and Science University, Portland, OR, USA
| | | | | | - Jacob Aelion
- West Tennessee Research Institute, Jackson, TN, USA
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Ghassem-Zadeh S, Gaida MM, Szanyi S, Acha-Orbea H, Frossard JL, Hinz U, Hackert T, Strobel O, Felix K. Distinct pathophysiological cytokine profiles for discrimination between autoimmune pancreatitis, chronic pancreatitis, and pancreatic ductal adenocarcinoma. J Transl Med 2017; 15:126. [PMID: 28578701 PMCID: PMC5457650 DOI: 10.1186/s12967-017-1227-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Accepted: 05/27/2017] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Discriminating between autoimmune pancreatitis (AIP), chronic pancreatitis (CP), and pancreatic ductal adenocarcinoma (PDAC) can be challenging. In this retrospective study, levels of serum and tissue cytokines were analyzed as part of the clinical strategy for the preoperative differentiation between AIP and PDAC. The identification of differential cytokine profiles may help to prevent unnecessary surgical resection and allow optimal treatment of these pathologies. METHODS To compare the cytokine profiles of AIP, CP, and PDAC patients, serum and pancreatic tissue homogenates were subjected to multiplex analysis of 17 inflammatory mediators. In total, serum from 73 patients, composed of 29 AIP (14 AIP-1 and 15 AIP-2), 17 CP, and 27 PDAC, and pancreatic tissue from 36 patients, including 12 AIP (six AIP-1 and six AIP-2), 12 CP, and 12 PDAC, were analyzed. RESULTS Comparing AIP and PDAC patients' serum, significantly higher concentrations were found in AIP for interleukins IL-1β, IL-7, IL-13, and granulocyte colony-stimulating factor (G-CSF). G-CSF also allowed discrimination of AIP from CP. Furthermore, once AIP was divided into subtypes, significantly higher serum levels for IL-7 and G-CSF were measured in both subtypes of AIP and in AIP-2 for IL-1β when compared to PDAC. G-CSF and TNF-α were also significantly differentially expressed in tissue homogenates between AIP-2 and PDAC. CONCLUSIONS The cytokines IL-1β, IL-7, and G-CSF can be routinely measured in patients' serum, providing an elegant and non-invasive approach for differential diagnosis. G-CSF is a good candidate to supplement the currently known serum markers in predictive tests for AIP and represents a basis for a combined blood test to differentiate AIP and particularly AIP-2 from PDAC, enhancing the possibility of appropriate treatment.
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Affiliation(s)
- Sahar Ghassem-Zadeh
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany
- Department of Biochemistry, University of Lausanne, Lausanne, Switzerland
| | - Matthias M. Gaida
- Institute of Pathology, University of Heidelberg, Heidelberg, Germany
| | - Szilard Szanyi
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany
| | - Hans Acha-Orbea
- Department of Biochemistry, University of Lausanne, Lausanne, Switzerland
| | - Jean-Louis Frossard
- Department of Medical Specialties, Gastroenterology and Hepatology Division, University Hospitals and Faculty of Medicine of Geneva, Geneva, Switzerland
| | - Ulf Hinz
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany
| | - Thilo Hackert
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany
| | - Oliver Strobel
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany
| | - Klaus Felix
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany
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Wang Y, Wu Q, Liu Z, Guo X, Zhou L, Wang Y, Song L, Wang N, Zheng Q, Wang W, Ren G, Li D. A recombinant IgG-like bispecific antibody acting as interleukin-1β and interleukin-17A inhibitor exhibits a promising efficacy for rheumatoid arthritis. Biomed Pharmacother 2017; 89:426-437. [DOI: 10.1016/j.biopha.2017.02.045] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2016] [Revised: 02/14/2017] [Accepted: 02/14/2017] [Indexed: 01/04/2023] Open
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Leblond A, Allanore Y, Avouac J. Targeting synovial neoangiogenesis in rheumatoid arthritis. Autoimmun Rev 2017; 16:594-601. [PMID: 28414154 DOI: 10.1016/j.autrev.2017.04.005] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Accepted: 03/03/2017] [Indexed: 12/18/2022]
Abstract
In Rheumatoid arthritis (RA), neoangiogenesis is an early and crucial event to promote the development of the hyperplasic proliferative pathologic synovium. Endothelial cells are critical for the formation of new blood vessels since they highly contribute to angiogenesis and vasculogenesis. Current therapies in RA target the inflammatory consequences of autoimmune activation and despite major improvements these last years still refractory patients or incomplete responders may be seen raising the point of the need to identify complementary additive and innovative therapies. This review resumes the mechanisms of synovial neoangiogenesis in RA, including recent insights on the implication of vasculogenesis, and the regulation of synovial neoangiogenesis by angiogenic and inflammatory mediators. In line with the recent development of vascular-targeted therapies used in cancer and beyond, we also discuss possible therapeutic implications in RA, in particular the combination of targeted immunotherapies with anti-angiogenic molecules.
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Affiliation(s)
- Agathe Leblond
- Université Paris Descartes, Sorbonne Paris Cité, INSERM U1016 and CNRS UMR8104, Institut Cochin, Paris, France
| | - Yannick Allanore
- Université Paris Descartes, Sorbonne Paris Cité, INSERM U1016 and CNRS UMR8104, Institut Cochin, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Service de Rhumatologie A, Hôpital Cochin, Paris, France
| | - Jérôme Avouac
- Université Paris Descartes, Sorbonne Paris Cité, INSERM U1016 and CNRS UMR8104, Institut Cochin, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Service de Rhumatologie A, Hôpital Cochin, Paris, France.
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15
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DAĞLI AF, KARATAŞ A, ORHAN C, TUZCU M, ÖZGEN M, ŞAHİN K, KOCA SS. Antiinflammatory and antioxidant effects of gemcitabinein collagen-induced arthritis model. Turk J Med Sci 2017; 47:1037-1044. [DOI: 10.3906/sag-1606-80] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Accepted: 12/13/2016] [Indexed: 11/03/2022] Open
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16
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Li SM, Yu YH, Li L, Wang WF, Li DS. Treatment of CIA Mice with FGF21 Down-regulates TH17-IL-17 Axis. Inflammation 2016; 39:309-319. [PMID: 26424095 DOI: 10.1007/s10753-015-0251-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Recently, FGF21 was reported to play an important role in anti-inflammation. The aim of the study is to explore the mechanism for FGF21 alleviating inflammation of CIA. CIA mice were injected with FGF21 once a day for 28 days after first booster immunization. The results showed that FGF21 alleviates arthritis severity and decreases serum anti-CII antibodies levels in CIA mice. Compared with CIA model, the number of the splenic TH17 cells was significantly decreased in FGF21-treated mice. FGF21 treatment reduced the mRNA expression of IL-17, TNF-α, IL-1β, IL-6, IL-8, and MMP3 and increased level of IL-10 in the spleen tissue. The expression of STAT3 and phosphorylated STAT3 was suppressed in FGF21-treated group. The mRNA expression of RORγt and IL-23 also decreased. In conclusion, these findings suggest that the beneficial effects of FGF21 on CIA mice were achieved by down-regulating Th17-IL-17 axis through STAT3/RORγt pathway. Modulating of Th17-mediated inflammatory response may be one of the mechanisms for FGF21 attenuating inflammation in CIA.
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Affiliation(s)
- Si-Ming Li
- Harbin University of Commerce, No. 1 Xuehai Street Songbei Distric, 150028, Harbin, Heilongjiang, China. .,School of Life Science, Northeast Agricultural University, No. 59 Mucai Street Xiangfang Distric, 150030, Harbin, Heilongjiang, China.
| | - Yin-Hang Yu
- School of Life Science, Northeast Agricultural University, No. 59 Mucai Street Xiangfang Distric, 150030, Harbin, Heilongjiang, China
| | - Lu Li
- School of Life Science, Northeast Agricultural University, No. 59 Mucai Street Xiangfang Distric, 150030, Harbin, Heilongjiang, China
| | - Wen-Fei Wang
- School of Life Science, Northeast Agricultural University, No. 59 Mucai Street Xiangfang Distric, 150030, Harbin, Heilongjiang, China
| | - De-Shan Li
- School of Life Science, Northeast Agricultural University, No. 59 Mucai Street Xiangfang Distric, 150030, Harbin, Heilongjiang, China.
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17
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Xue X, Soroosh P, De Leon-Tabaldo A, Luna-Roman R, Sablad M, Rozenkrants N, Yu J, Castro G, Banie H, Fung-Leung WP, Santamaria-Babi L, Schlueter T, Albers M, Leonard K, Budelsky AL, Fourie AM. Pharmacologic modulation of RORγt translates to efficacy in preclinical and translational models of psoriasis and inflammatory arthritis. Sci Rep 2016; 6:37977. [PMID: 27905482 PMCID: PMC5131364 DOI: 10.1038/srep37977] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Accepted: 10/27/2016] [Indexed: 12/14/2022] Open
Abstract
The IL-23/IL-17 pathway is implicated in autoimmune diseases, particularly psoriasis, where biologics targeting IL-23 and IL-17 have shown significant clinical efficacy. Retinoid-related orphan nuclear receptor gamma t (RORγt) is required for Th17 differentiation and IL-17 production in adaptive and innate immune cells. We identified JNJ-54271074, a potent and highly-selective RORγt inverse agonist, which dose-dependently inhibited RORγt-driven transcription, decreased co-activator binding and promoted interaction with co-repressor protein. This compound selectively blocked Th17 differentiation, significantly reduced IL-17A production from memory T cells, and decreased IL-17A- and IL-22-producing human and murine γδ and NKT cells. In a murine collagen-induced arthritis model, JNJ-54271074 dose-dependently suppressed joint inflammation. Furthermore, JNJ-54271074 suppressed IL-17A production in human PBMC from rheumatoid arthritis patients. RORγt-deficient mice showed decreased IL-23-induced psoriasis-like skin inflammation and cytokine gene expression, consistent with dose-dependent inhibition in wild-type mice through oral dosing of JNJ-54271074. In a translational model of human psoriatic epidermal cells and skin-homing T cells, JNJ-54271074 selectively inhibited streptococcus extract-induced IL-17A and IL-17F. JNJ-54271074 is thus a potent, selective RORγt modulator with therapeutic potential in IL-23/IL-17 mediated autoimmune diseases.
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MESH Headings
- Administration, Oral
- Animals
- Arthritis, Rheumatoid/drug therapy
- Arthritis, Rheumatoid/genetics
- Arthritis, Rheumatoid/metabolism
- Cell Differentiation/drug effects
- Cells, Cultured
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Gene Expression Regulation/drug effects
- Interleukin-17/metabolism
- Interleukins/metabolism
- Mice
- Nuclear Receptor Subfamily 1, Group F, Member 3/genetics
- Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism
- Peptides, Cyclic/administration & dosage
- Peptides, Cyclic/pharmacology
- Psoriasis/drug therapy
- Psoriasis/genetics
- Psoriasis/metabolism
- Th17 Cells/cytology
- Th17 Cells/drug effects
- Th17 Cells/metabolism
- Transcription, Genetic
- Interleukin-22
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Affiliation(s)
- Xiaohua Xue
- Janssen Research & Development, La Jolla, California, United States
| | - Pejman Soroosh
- Janssen Research & Development, La Jolla, California, United States
| | | | - Rosa Luna-Roman
- Janssen Research & Development, La Jolla, California, United States
| | - Marciano Sablad
- Janssen Research & Development, La Jolla, California, United States
| | | | - Jingxue Yu
- Janssen Research & Development, La Jolla, California, United States
| | - Glenda Castro
- Janssen Research & Development, La Jolla, California, United States
| | - Homayon Banie
- Janssen Research & Development, La Jolla, California, United States
| | | | - Luis Santamaria-Babi
- Translational Immunology (PCB/UB), Department of Physiology and Immunology, Universitat de Barcelona Barcelona, Spain
| | - Thomas Schlueter
- Department of Research, Phenex Pharmaceuticals AG, Heidelberg, Germany
| | - Michael Albers
- Department of Research, Phenex Pharmaceuticals AG, Heidelberg, Germany
| | - Kristi Leonard
- Janssen Research & Development, Spring House, Pennsylvania, United States
| | | | - Anne M. Fourie
- Janssen Research & Development, La Jolla, California, United States
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New roles for CD14 and IL-β linking inflammatory dendritic cells to IL-17 production in memory CD4 + T cells. Immunol Cell Biol 2016; 94:907-916. [PMID: 27550748 DOI: 10.1038/icb.2016.66] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Revised: 07/15/2016] [Accepted: 07/16/2016] [Indexed: 02/06/2023]
Abstract
Interleukin (IL)-1β has proven to be crucial in the differentiation of human and mouse Th17 cells. Although it has become evident that IL-1β has potent IL-17-inducing effects on CD4+ T cells directly, it has not yet been explored whether IL-1β can also prime dendritic cells (DCs) for a Th17 instruction program. Here, we show that human immature DCs exposed to IL-1β promote IL-17 production in human memory CD4+ T cells. IL-1β-primed DCs express high levels of CD14 that mediate IL-17 production through direct interaction with T cells. Moreover, culturing human CD4+CD45RO+ memory T cells with soluble CD14 is sufficient for the upregulation of retinoic acid-related orphan receptor-γ thymus and IL-17 production. In addition, in a human in situ model using tissue-resident skin DCs, upregulation of CD14 expression induced by IL-1β on skin residents DCs promotes IL-17 production in memory T cells; strongly suggesting the in vivo relevance of this mechanism. Our findings uncover new roles for IL-1β and CD14, and may therefore have important consequences for the development of new therapies for Th17-mediated autoimmune diseases and bacterial and fungal pathogenic infections.
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19
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Jung HW, Kim KH, Park YK. Inhibitory effect of the extract of Phellodendron amurense ruprecht root on collagen-induced arthritis in mice. Chin J Integr Med 2016; 23:755-762. [PMID: 27460490 DOI: 10.1007/s11655-016-2094-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2013] [Indexed: 01/08/2023]
Abstract
OBJECTIVE To investigate whether the dried root of Phellodendron amurense Ruprecht (Phellodendri cortex; PC) extract improves arthritic symptoms through anti-inflammatory and immune-modulatory effects in collagen-induced arthritis in mice. METHODS Rheumatoid arthritis (RA) was induced in male DBA/1 mice by immunization with type II collagen (ColII). CIA mice were divided into 5 groups (n=10 per a group) with normal, CIA control, PC extract (50 mg/kg and 100 mg/kg)-treated, and meloxicam (50 mg/kg)-treated as the reference drug. The PC extract or meloxicam were administered orally in CIA mice once a day for 14 days after arthritis induction. Arthritic score, levels of anti-ColII IgG2a antibody, prostaglandin E2 (PGE2), tumor necrosis factor (TNF)-α, and interleukin (IL)-17 in the sera of CIA mice were measured. Histopathological changes in the ankle joints of CIA mice were also analyzed by staining with hematoxylin and eosin (H and E), safranin-O and immunohistochemistry using anti-TNF-α and anti-IL-17 antibodies. RESULTS The arthritic score was increased in CIA mice in a time-dependent manner, as were the serum levels of anti-ColII IgG2a antibody, PGE2, TNF-α, and IL-17. However, the oral administration of PC extract at 50 and 100 mg/kg in CIA mice significantly decreased the arthritic scores, and the serum levels of anti-ColII IgG2a, PGE2, TNF-α, and IL-17 compared with those in the CIA group (P<0.05 or P<0.01). Furthermore, histopathological improvement of the joint architecture in CIA mice was observed after administration of PC extract. PC extract also significantly inhibited the expression of TNF-α and IL-17 in the joints of CIA mice by suppressing the expression of their mRNA and proteins. CONCLUSION PC extract may improve the pathological progression of RA through the inhibition of joint destruction by synovial inflammation and immune-stimulation, therefore, it would be a potential anti-arthritic agent in RA.
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Affiliation(s)
- Hyo Won Jung
- Department of Herbology, College of Korean Medicine, Dongguk University, Gyeongju, 740-814, Republic of Korea.
- Korean Medicine Research and Development Center, Dongguk University, Gyeongju, 740-814, Republic of Korea.
| | - Kyung-Ho Kim
- Department of Acupuncture, College of Korean Medicine, Dongguk University, Gyeongju, 740-814, Republic of Korea
| | - Yong-Ki Park
- Department of Herbology, College of Korean Medicine, Dongguk University, Gyeongju, 740-814, Republic of Korea
- Korean Medicine Research and Development Center, Dongguk University, Gyeongju, 740-814, Republic of Korea
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20
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Externalized decondensed neutrophil chromatin occludes pancreatic ducts and drives pancreatitis. Nat Commun 2016; 7:10973. [PMID: 26964500 PMCID: PMC4793047 DOI: 10.1038/ncomms10973] [Citation(s) in RCA: 175] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2015] [Accepted: 02/08/2016] [Indexed: 02/07/2023] Open
Abstract
Ductal occlusion has been postulated to precipitate focal pancreatic inflammation,
while the nature of the primary occluding agents has remained elusive. Neutrophils
make use of histone citrullination by peptidyl arginine deiminase-4 (PADI4) in
contact to particulate agents to extrude decondensed chromatin as neutrophil
extracellular traps (NETs). In high cellular density, NETs form macroscopically
visible aggregates. Here we show that such aggregates form inside pancreatic ducts
in humans and mice occluding pancreatic ducts and thereby driving pancreatic
inflammation. Experimental models indicate that PADI4 is critical for intraductal
aggregate formation and that PADI4-deficiency abrogates disease progression.
Mechanistically, we identify the pancreatic juice as a strong instigator of
neutrophil chromatin extrusion. Characteristic single components of pancreatic
juice, such as bicarbonate ions and calcium carbonate crystals, induce aggregated
NET formation. Ductal occlusion by aggregated NETs emerges as a pathomechanism with
relevance in a plethora of inflammatory conditions involving secretory ducts. Pancreatitis often develops as a consequence of ductal obstruction.
Here, the authors show that bicarbonate ions initiate the release of neutrophil
extracellular traps (NETs) that form pancreatic ductal aggregates and occlude the ducts,
thereby driving pancreatitis in mice and humans.
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Tlustochowicz W, Rahman P, Seriolo B, Krammer G, Porter B, Widmer A, Richards HB. Efficacy and Safety of Subcutaneous and Intravenous Loading Dose Regimens of Secukinumab in Patients with Active Rheumatoid Arthritis: Results from a Randomized Phase II Study. J Rheumatol 2016; 43:495-503. [PMID: 26834211 DOI: 10.3899/jrheum.150117] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/08/2015] [Indexed: 12/14/2022]
Abstract
OBJECTIVE To evaluate the efficacy and safety of secukinumab, a fully human antiinterleukin-17A monoclonal antibody, administered with an intravenous (IV) or subcutaneous (SC) loading regimen versus placebo, in patients with active rheumatoid arthritis (RA). METHODS In this phase II, double-blind, double-dummy, 52-week study (ClinicalTrials.gov NCT01359943), 221 patients with inadequate response to methotrexate were randomized (2:2:1) to secukinumab, IV loading 10 mg/kg at baseline, Weeks 2 and 4, then SC 150 mg every 4 weeks (n = 88); secukinumab SC loading 150 mg once weekly for 5 weeks, then every 4 weeks (n = 89); or a matching placebo (followed by secukinumab 150 mg every 4 weeks starting Week 16; n = 44). The primary endpoint was superior efficacy of pooled secukinumab versus placebo using American College of Rheumatology 20% response (ACR20) at Week 12. RESULTS The primary efficacy endpoint was not met: ACR20 response at Week 12 was 49.2% for pooled secukinumab versus 40.9% for placebo (p = 0.3559). These variables improved significantly with pooled secukinumab versus placebo at Week 12 (all p < 0.05): the 28-joint Disease Activity Score (DAS28), patient's and physician's global assessment of disease activity, patient's assessment of RA pain, and high-sensitivity C-reactive protein levels. Results of continuous efficacy outcomes were similar between the IV and SC loading regimens. The most frequent adverse events were infections, with similar rates across secukinumab and placebo. CONCLUSION Although the primary endpoint (ACR20) was not met, secukinumab demonstrated improved efficacy in reducing disease activity over placebo as measured by DAS28 and other secondary endpoints.
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Affiliation(s)
- Witold Tlustochowicz
- From the Klinika Chorob Wewnetrznych i Reumatologii, Centralny Szpital Kliniczny MON Wojskowy Instytut Medyczny, Warsaw, Poland; Memorial University, St. John's, Newfoundland, Canada; Department of Internal Medicine, Research Laboratory and Academic Unit of Clinical Rheumatology, University of Genoa, Genoa, Italy; Novartis Pharma AG, Basel, Switzerland; and Novartis Pharmaceutical Corporation, East Hanover, New Jersey, USA.W. Tlustochowicz, MD, PhD, Klinika Chorob Wewnetrznych i Reumatologii, Centralny Szpital Kliniczny MON Wojskowy Instytut Medyczny; P. Rahman, MD, FRCPC, Memorial University; B. Seriolo, MD, Department of Internal Medicine, Research Laboratory and Academic Unit of Clinical Rheumatology, University of Genoa;G. Krammer, MS; A. Widmer, MSc; H.B. Richards, MD, Novartis Pharma AG; B. Porter, MD, PhD, MPH, Novartis Pharmaceutical Corporation.
| | - Proton Rahman
- From the Klinika Chorob Wewnetrznych i Reumatologii, Centralny Szpital Kliniczny MON Wojskowy Instytut Medyczny, Warsaw, Poland; Memorial University, St. John's, Newfoundland, Canada; Department of Internal Medicine, Research Laboratory and Academic Unit of Clinical Rheumatology, University of Genoa, Genoa, Italy; Novartis Pharma AG, Basel, Switzerland; and Novartis Pharmaceutical Corporation, East Hanover, New Jersey, USA.W. Tlustochowicz, MD, PhD, Klinika Chorob Wewnetrznych i Reumatologii, Centralny Szpital Kliniczny MON Wojskowy Instytut Medyczny; P. Rahman, MD, FRCPC, Memorial University; B. Seriolo, MD, Department of Internal Medicine, Research Laboratory and Academic Unit of Clinical Rheumatology, University of Genoa;G. Krammer, MS; A. Widmer, MSc; H.B. Richards, MD, Novartis Pharma AG; B. Porter, MD, PhD, MPH, Novartis Pharmaceutical Corporation
| | - Bruno Seriolo
- From the Klinika Chorob Wewnetrznych i Reumatologii, Centralny Szpital Kliniczny MON Wojskowy Instytut Medyczny, Warsaw, Poland; Memorial University, St. John's, Newfoundland, Canada; Department of Internal Medicine, Research Laboratory and Academic Unit of Clinical Rheumatology, University of Genoa, Genoa, Italy; Novartis Pharma AG, Basel, Switzerland; and Novartis Pharmaceutical Corporation, East Hanover, New Jersey, USA.W. Tlustochowicz, MD, PhD, Klinika Chorob Wewnetrznych i Reumatologii, Centralny Szpital Kliniczny MON Wojskowy Instytut Medyczny; P. Rahman, MD, FRCPC, Memorial University; B. Seriolo, MD, Department of Internal Medicine, Research Laboratory and Academic Unit of Clinical Rheumatology, University of Genoa;G. Krammer, MS; A. Widmer, MSc; H.B. Richards, MD, Novartis Pharma AG; B. Porter, MD, PhD, MPH, Novartis Pharmaceutical Corporation
| | - Gerhard Krammer
- From the Klinika Chorob Wewnetrznych i Reumatologii, Centralny Szpital Kliniczny MON Wojskowy Instytut Medyczny, Warsaw, Poland; Memorial University, St. John's, Newfoundland, Canada; Department of Internal Medicine, Research Laboratory and Academic Unit of Clinical Rheumatology, University of Genoa, Genoa, Italy; Novartis Pharma AG, Basel, Switzerland; and Novartis Pharmaceutical Corporation, East Hanover, New Jersey, USA.W. Tlustochowicz, MD, PhD, Klinika Chorob Wewnetrznych i Reumatologii, Centralny Szpital Kliniczny MON Wojskowy Instytut Medyczny; P. Rahman, MD, FRCPC, Memorial University; B. Seriolo, MD, Department of Internal Medicine, Research Laboratory and Academic Unit of Clinical Rheumatology, University of Genoa;G. Krammer, MS; A. Widmer, MSc; H.B. Richards, MD, Novartis Pharma AG; B. Porter, MD, PhD, MPH, Novartis Pharmaceutical Corporation
| | - Brian Porter
- From the Klinika Chorob Wewnetrznych i Reumatologii, Centralny Szpital Kliniczny MON Wojskowy Instytut Medyczny, Warsaw, Poland; Memorial University, St. John's, Newfoundland, Canada; Department of Internal Medicine, Research Laboratory and Academic Unit of Clinical Rheumatology, University of Genoa, Genoa, Italy; Novartis Pharma AG, Basel, Switzerland; and Novartis Pharmaceutical Corporation, East Hanover, New Jersey, USA.W. Tlustochowicz, MD, PhD, Klinika Chorob Wewnetrznych i Reumatologii, Centralny Szpital Kliniczny MON Wojskowy Instytut Medyczny; P. Rahman, MD, FRCPC, Memorial University; B. Seriolo, MD, Department of Internal Medicine, Research Laboratory and Academic Unit of Clinical Rheumatology, University of Genoa;G. Krammer, MS; A. Widmer, MSc; H.B. Richards, MD, Novartis Pharma AG; B. Porter, MD, PhD, MPH, Novartis Pharmaceutical Corporation
| | - Albert Widmer
- From the Klinika Chorob Wewnetrznych i Reumatologii, Centralny Szpital Kliniczny MON Wojskowy Instytut Medyczny, Warsaw, Poland; Memorial University, St. John's, Newfoundland, Canada; Department of Internal Medicine, Research Laboratory and Academic Unit of Clinical Rheumatology, University of Genoa, Genoa, Italy; Novartis Pharma AG, Basel, Switzerland; and Novartis Pharmaceutical Corporation, East Hanover, New Jersey, USA.W. Tlustochowicz, MD, PhD, Klinika Chorob Wewnetrznych i Reumatologii, Centralny Szpital Kliniczny MON Wojskowy Instytut Medyczny; P. Rahman, MD, FRCPC, Memorial University; B. Seriolo, MD, Department of Internal Medicine, Research Laboratory and Academic Unit of Clinical Rheumatology, University of Genoa;G. Krammer, MS; A. Widmer, MSc; H.B. Richards, MD, Novartis Pharma AG; B. Porter, MD, PhD, MPH, Novartis Pharmaceutical Corporation
| | - Hanno B Richards
- From the Klinika Chorob Wewnetrznych i Reumatologii, Centralny Szpital Kliniczny MON Wojskowy Instytut Medyczny, Warsaw, Poland; Memorial University, St. John's, Newfoundland, Canada; Department of Internal Medicine, Research Laboratory and Academic Unit of Clinical Rheumatology, University of Genoa, Genoa, Italy; Novartis Pharma AG, Basel, Switzerland; and Novartis Pharmaceutical Corporation, East Hanover, New Jersey, USA.W. Tlustochowicz, MD, PhD, Klinika Chorob Wewnetrznych i Reumatologii, Centralny Szpital Kliniczny MON Wojskowy Instytut Medyczny; P. Rahman, MD, FRCPC, Memorial University; B. Seriolo, MD, Department of Internal Medicine, Research Laboratory and Academic Unit of Clinical Rheumatology, University of Genoa;G. Krammer, MS; A. Widmer, MSc; H.B. Richards, MD, Novartis Pharma AG; B. Porter, MD, PhD, MPH, Novartis Pharmaceutical Corporation
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Pietrosimone KM, Liu P. Contributions of neutrophils to the adaptive immune response in autoimmune disease. World J Transl Med 2015; 4:60-68. [PMID: 27042404 PMCID: PMC4816207 DOI: 10.5528/wjtm.v4.i3.60] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Revised: 10/01/2015] [Accepted: 11/25/2015] [Indexed: 02/05/2023] Open
Abstract
Neutrophils are granulocytic cytotoxic leukocytes of the innate immune system that activate during acute inflammation. Neutrophils can also persist beyond the acute phase of inflammation to impact the adaptive immune response during chronic inflammation. In the context of the autoimmune disease, neutrophils modulating T and B cell functions by producing cytokines and chemokines, forming neutrophil extracellular traps, and acting as or priming antigen presentation cells. Thus, neutrophils are actively involved in chronic inflammation and tissue damage in autoimmune disease. Using rheumatoid arthritis as an example, this review focuses on functions of neutrophils in adaptive immunity and the therapeutic potential of these cells in the treatment of autoimmune disease and chronic inflammation.
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MDM2 promotes rheumatoid arthritis via activation of MAPK and NF-κB. Int Immunopharmacol 2015; 30:69-73. [PMID: 26655743 DOI: 10.1016/j.intimp.2015.11.030] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Revised: 11/15/2015] [Accepted: 11/23/2015] [Indexed: 12/19/2022]
Abstract
Murine double minute-2 (MDM2) has pleiotropic roles in immune activation and regulation. However, the role of MDM2 in rheumatoid arthritis (RA) remains unknown. We undertook this study to investigate the role of MDM2 in rheumatoid arthritis (RA). Fibroblast-like synoviocytes (FLS) were isolated from 25 patients with active RA and 25 patients with osteoarthritis (OA). FLS were stimulated in the presence or absence of IL-1β in vitro. Mice with collagen-induced arthritis (CIA) were treated with Nutlin-3a (100mg/kg) or vehicle twice daily for 2weeks. MDM2 expression was determined by Western blot. MDM2 was down-regulated by specific gene silencing. The concentrations of pro-inflammatory cytokines and matrix metalloproteinases (MMPs) were analyzed using enzyme-linked immunosorbent assay (ELISA). The pathways of mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) were investigated by Western blot. Arthritis scoring and histological analysis were conducted. MDM2 expression was significantly higher in RA-FLS than in OA-FLS. MDM2 protein expression was positively correlated with disease activity of RA. MDM2 promoted the production of TNF-α, IL-6, MMP1 and MMP13 through MAPK and NF-κB pathways in RA-FLS. Nutlin-3a treatment decreased the arthritis severity and joint damage in CIA. Nutlin-3a also inhibited the activation of MAPK and NF-κB in arthritic joints. In conclusion, MDM2 inhibition exhibits anti-inflammatory activity and MDM2 might be a new therapeutic target for RA.
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Hu Y, Wang X, Wu Y, Jin W, Cheng B, Fang X, Martel-Pelletier J, Kapoor M, Peng J, Qi S, Shi G, Wu J, Luo H. Role of EFNB1 and EFNB2 in Mouse Collagen-Induced Arthritis and Human Rheumatoid Arthritis. Arthritis Rheumatol 2015; 67:1778-88. [PMID: 25779027 DOI: 10.1002/art.39116] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2014] [Accepted: 03/10/2015] [Indexed: 02/05/2023]
Abstract
OBJECTIVE EFNB1 and EFNB2 are ligands for Eph receptor tyrosine kinases. This study was undertaken to investigate how the expression of Efnb1 and Efnb2 on murine T cells influences the pathogenesis of collagen-induced arthritis (CIA) and to assess correlations between the T cell expression of these 2 molecules and measures of disease activity in patients with rheumatoid arthritis (RA). METHODS CIA was studied in mice with T cell-specific deletion (double gene knockout [dKO]) of both Efnb1 and Efnb2. Expression of EFNB1 and EFNB2 messenger RNA (mRNA) in peripheral blood T cells from patients with RA was determined by quantitative reverse transcription- polymerase chain reaction. RESULTS In dKO mice, clinical scores of arthritis were reduced compared to those in wild-type (WT) control mice. Serum collagen-specific antibody titers in dKO mice were lower than those in WT mice. In analyses based on equal cell numbers, dKO mouse T cells, as compared to WT mouse T cells, provided vastly inferior help to B cells in the production of collagen-specific antibodies in vitro. T cells from dKO mice were compromised in their ability to migrate to the arthritic paws in vivo and in their ability to undergo chemotaxis toward CXCL12 in vitro. Deletion mutation of Efnb1 and Efnb2 intracellular tails revealed critical regions in controlling T cell chemotaxis. T cells from RA patients expressed higher EFNB1 mRNA levels, which correlated with RA symptoms and laboratory findings. CONCLUSION Efnb1 and Efnb2 in T cells are essential for pathogenic antibody production and for T cell migration to the inflamed paws in mice with CIA. These findings suggest that the expression of EFNB1 in T cells might be a useful parameter for monitoring RA disease activity and treatment responses.
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Affiliation(s)
- Yan Hu
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada
| | - Xuehai Wang
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada
| | - Yongqiang Wu
- West China Hospital of Sichuan University, Chengdu, China
| | - Wei Jin
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada
| | - Baoli Cheng
- First Affiliated Hospital of Zhejiang University, Hangzhou, China
| | - Xiangming Fang
- First Affiliated Hospital of Zhejiang University, Hangzhou, China
| | | | - Mohit Kapoor
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada
| | - Junzheng Peng
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada
| | - Shijie Qi
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada
| | - Guixiu Shi
- First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Jiangping Wu
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada
| | - Hongyu Luo
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada
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Andersson KME, Cavallini NF, Hu D, Brisslert M, Cialic R, Valadi H, Erlandsson MC, Silfverswärd S, Pullerits R, Kuchroo VK, Weiner HL, Bokarewa MI. Pathogenic Transdifferentiation of Th17 Cells Contribute to Perpetuation of Rheumatoid Arthritis during Anti-TNF Treatment. Mol Med 2015; 21:536-543. [PMID: 26062018 PMCID: PMC4607618 DOI: 10.2119/molmed.2015.00057] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2015] [Accepted: 06/02/2015] [Indexed: 12/21/2022] Open
Abstract
T-helper cells producing interleukin (IL)-17A and IL-17F cytokines (Th17 cells) are considered the source of autoimmunity in rheumatoid arthritis (RA). In this study, we characterized specific pathogenic features of Th17 cells in RA. By using nano-string technology, we analyzed transcription of 419 genes in the peripheral blood CCR6(+)CXCR3(-) CD4(+) cells of 14 RA patients and 6 healthy controls and identified 109 genes discriminating Th17 cells of RA patients from the controls. Th17 cells of RA patients had an aggressive pathogenic profile and in addition to signature cytokines IL-17, IL-23 and IL-21, and transcriptional regulators RAR-related orphan receptor gamma of T cells (RORγt) and Janus kinase 2 (JAK2), they produced high levels of IL-23R, C-C chemokine ligand type 20 (CCL20), granulocyte-monocyte colony-stimulating factor (GM-CSF ) and transcription factor Tbet required for synovial homing. We showed that Th17 cells are enriched with Helios-producing Foxp3- and IL2RA-deficient cells, indicating altered regulatory profile. The follicular T-helper (Tfh) cells presented a functional profile of adaptor molecules, transcriptional regulator Bcl-6 and B-cell activating cytokines IL-21, IL-31 and leukemia inhibitory factor (LIF ). We observed that anti-tumor necrosis factor (TNF) treatment had a limited effect on the transcription signature of Th17 cells. Patients in remission retained the machinery of receptors (IL-23R and IL-1R1), proinflammatory cytokines (IL-17F, IL-23, IL-21 and TNF ) and adaptor molecules (C-X-C chemokine receptor 5 [CXCR5] and cytotoxic T-lymphocyte-associated protein 4 [CTLA-4]), essential for efficient transdifferentiation and accumulation of Th17 cells. This study convincingly shows that the peripheral blood CCR6(+)CXCR3(-) CD4(+) cells of RA patients harbor pathogenic subsets of Th17 and Tfh cells, which may transdifferentiate from Tregs and contribute to perpetuation of the disease.
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Affiliation(s)
- Karin M E Andersson
- Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, Gothenburg University, Gothenburg, Sweden
| | - Nicola Filluelo Cavallini
- Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, Gothenburg University, Gothenburg, Sweden
| | - Dan Hu
- Center for Neurologic Diseases, Brigham & Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Mikael Brisslert
- Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, Gothenburg University, Gothenburg, Sweden
| | - Ron Cialic
- Center for Neurologic Diseases, Brigham & Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Hadi Valadi
- Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, Gothenburg University, Gothenburg, Sweden
| | - Malin C Erlandsson
- Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, Gothenburg University, Gothenburg, Sweden
| | - Sofia Silfverswärd
- Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, Gothenburg University, Gothenburg, Sweden
| | - Rille Pullerits
- Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, Gothenburg University, Gothenburg, Sweden
| | - Vijay K Kuchroo
- Center for Neurologic Diseases, Brigham & Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Howard L Weiner
- Center for Neurologic Diseases, Brigham & Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Maria I Bokarewa
- Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, Gothenburg University, Gothenburg, Sweden
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26
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Blockade of 11β-hydroxysteroid dehydrogenase type 1 enzyme inhibits experimental collagenase-induced osteoarthritis. Mol Med Rep 2015; 11:2071-5. [DOI: 10.3892/mmr.2014.2983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2014] [Accepted: 09/24/2014] [Indexed: 01/15/2023] Open
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Inhibition of P2X4 suppresses joint inflammation and damage in collagen-induced arthritis. Inflammation 2014; 37:146-53. [PMID: 24062058 DOI: 10.1007/s10753-013-9723-y] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Recent data have shown that the purinergic receptor P2X4 plays key roles in inflammatory responses. We evaluated whether P2X4 inhibition could affect the development of arthritis and autoimmunity in collagen-induced arthritis (CIA) model. P2X4 antisense oligonucleotide (asODN) was injected intravenously via tail vein into the CIA mice to selectively inhibit P2X4 expression daily for 14 days. P2X4 asODN treatment reduced the clinical score of CIA in mice. P2X4 asODN also decreased the levels of serum IL-1β, TNF-α, IL-6, and IL-17. P2X4 asODN treatment significantly inhibited synovial inflammation and joint destruction. P2X4 asODN treatment also suppressed the NLR family, pyrin domain containing 1 (NLRP1) inflammasome activation in CIA mice and synovial cells of human rheumatoid arthritis. These data show that P2X4 asODN confers a therapeutic benefit on CIA. Inhibition of the NLRP1 inflammasome signaling pathway is the underlying mechanism of action.
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Kuncirova V, Ponist S, Mihalova D, Drafi F, Nosal R, Acquaviva A, Gardi C, Harmatha J, Hradkova I, Bauerova K. N-feruloylserotonin in preventive combination therapy with methotrexate reduced inflammation in adjuvant arthritis. Fundam Clin Pharmacol 2014; 28:616-26. [DOI: 10.1111/fcp.12085] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2014] [Revised: 05/22/2014] [Accepted: 06/06/2014] [Indexed: 12/31/2022]
Affiliation(s)
- Viera Kuncirova
- Institute of Experimental Pharmacology and Toxicology; Slovak Academy of Sciences; Dubravska cesta 9 SK-841 04 Bratislava Slovak Republic
| | - Silvester Ponist
- Institute of Experimental Pharmacology and Toxicology; Slovak Academy of Sciences; Dubravska cesta 9 SK-841 04 Bratislava Slovak Republic
| | - Danica Mihalova
- Institute of Experimental Pharmacology and Toxicology; Slovak Academy of Sciences; Dubravska cesta 9 SK-841 04 Bratislava Slovak Republic
| | - Frantisek Drafi
- Institute of Experimental Pharmacology and Toxicology; Slovak Academy of Sciences; Dubravska cesta 9 SK-841 04 Bratislava Slovak Republic
| | - Radomir Nosal
- Institute of Experimental Pharmacology and Toxicology; Slovak Academy of Sciences; Dubravska cesta 9 SK-841 04 Bratislava Slovak Republic
| | - Alessandra Acquaviva
- Department of Molecular and Developmental Medicine; University of Siena; via A. Moro - Loc. S. Miniato I-53100 Siena Italy
| | - Concetta Gardi
- Department of Molecular and Developmental Medicine; University of Siena; via A. Moro - Loc. S. Miniato I-53100 Siena Italy
| | - Juraj Harmatha
- Institute of Organic Chemistry and Biochemistry v.v.i.; AS CR; Flemingovo nam. 2 CZ - 166 10 Prague 6 Czech Republic
| | - Iveta Hradkova
- Department of Diary and Fat Technology; Faculty of Food and Biochemical Technology; Institute of Chemical Technology; Technicka 5 CZ - 166 28 Prague Czech Republic
| | - Katarina Bauerova
- Institute of Experimental Pharmacology and Toxicology; Slovak Academy of Sciences; Dubravska cesta 9 SK-841 04 Bratislava Slovak Republic
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Xue Y, Yang Y, Su Z, Barnie PA, Zheng D, Zhang Y, Xu Y, Wang S, Xu H. Local delivery of T-bet shRNA reduces inflammation in collagen II-induced arthritis via downregulation of IFN-γ and IL-17. Mol Med Rep 2014; 9:899-903. [PMID: 24425064 DOI: 10.3892/mmr.2014.1893] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2013] [Accepted: 01/06/2014] [Indexed: 11/06/2022] Open
Abstract
Th1 and Th17 cells are involved in the pathogenesis of rheumatoid arthritis (RA). T-bet, a Th1-specific transcription factor, appears to drive the maturation of Th1 and IFN-γ secretion. In the present study, we established the T-bet shRNA recombinant plasmid (p-T-shRNA) and explored its possible anti-inflammatory effect in a collagen-induced arthritis (CIA) model by local injection of plasmid vectors. For the initiation of CIA, DBA/1J mice were immunized with type II collagen (CII) in Freund's adjuvant and the CII-immunized mice were treated with p-T-shRNA. Levels of T-bet, IFN-γ, IL-17 and RORγt mRNA in splenocytes and synovial joints were measured by quantitative real-time PCR and T-bet expression in joint tissue was detected by immunohistochemistry staining. The intracellular IFN-γ and IL-17 were analyzed by flow cytometry (FCM). The results demonstrated that therapeutic administration on the local joints with p-T-shRNA significantly suppressed IFN-γ and IL-17 gene expression and improved the pathogenesis of arthritis in CIA mice, while administration of a plasmid expressing T-bet (pIRES-T-bet) accelerated the disease onset. Our study suggests that T-bet may be developed as a potential target for arthritis therapy.
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Affiliation(s)
- Yuan Xue
- Department of Immunology, Institute of Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Yong Yang
- The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, P.R. China
| | - Zhaoliang Su
- Department of Immunology, Institute of Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Prince Amoatt Barnie
- Department of Immunology, Institute of Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Dong Zheng
- Department of Immunology, Institute of Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Yun Zhang
- Department of Immunology, Institute of Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Yan Xu
- Department of Immunology, Institute of Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Shengjun Wang
- Department of Immunology, Institute of Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Huaxi Xu
- Department of Immunology, Institute of Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
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Wang X, Hu Y, Charpentier T, Lamarre A, Qi S, Wu J, Luo H. TNF-like Ligand 1A (TL1A) Gene Knockout Leads to Ameliorated Collagen-Induced Arthritis in Mice: Implication of TL1A in Humoral Immune Responses. THE JOURNAL OF IMMUNOLOGY 2013; 191:5420-9. [DOI: 10.4049/jimmunol.1301475] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
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Zhang L, Dong Y, Zou F, Wu M, Fan C, Ding Y. 11β-Hydroxysteroid dehydrogenase 1 inhibition attenuates collagen-induced arthritis. Int Immunopharmacol 2013; 17:489-94. [PMID: 23938253 DOI: 10.1016/j.intimp.2013.07.015] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2013] [Revised: 07/23/2013] [Accepted: 07/24/2013] [Indexed: 12/01/2022]
Abstract
11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) plays an important role in inflammation. However, the role of 11β-HSD1 in rheumatoid arthritis (RA) remains unknown. The purpose of this study was to evaluate the therapeutic effects of a selective 11β-HSD1 inhibitor BVT-2733 in collagen-induced arthritis (CIA) and its underlying mechanisms. CIA mice were treated with BVT-2733 (100 mg/kg, orally) or vehicle twice daily for 2 weeks. Arthritis score and joint histology were investigated. The levels of pro-inflammatory cytokines as well as anti-type II collagen antibody (anti-CII) were detected by ELISA. Western blot analysis was used to assess the activation of NF-κB and NLRP1 inflammasome in joint tissues and in human RA synovial cells. BVT-2733 treatment attenuated the arthritis severity and anti-CII level in CIA mice. BVT-2733 also decreased the levels of serum TNF-α, IL-1β, IL-6 and IL-17. BVT-2733 treatment also significantly reduced synovial inflammation and joint destruction. NF-κB activation and NLRP1 inflammasome assembly were also inhibited in arthritic joints and human RA synovial cells. In conclusion, BVT-2733 exhibits an anti-inflammatory effect on CIA. This protective effect is, at least partly, mediated by inhibition of the NF-κB and NLRP1 inflammasome signaling pathways. 11β-HSD1 inhibition may represent a potential therapeutic target for RA patients.
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Affiliation(s)
- Lei Zhang
- Department of Nephrology, The General Hospital of Jinan Military Command, Jinan, China
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Kong S, Yeung P, Fang D. The class III histone deacetylase sirtuin 1 in immune suppression and its therapeutic potential in rheumatoid arthritis. J Genet Genomics 2013; 40:347-54. [PMID: 23876775 PMCID: PMC4007159 DOI: 10.1016/j.jgg.2013.04.001] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2013] [Revised: 02/18/2013] [Accepted: 04/07/2013] [Indexed: 11/27/2022]
Abstract
Rheumatoid arthritis (RA) is a chronic debilitating disease of the joints. Both the innate and adaptive immune responses participate in the development and progression of RA. While several therapeutic reagents, such as TNF-α agonists, have been successfully developed for the clinical use in the treatment of RA, more than half of the patients do not respond to anti-TNF therapy. Therefore, new therapeutic reagents are needed. Recent studies have shown that sirtuin 1 (Sirt1), a nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylase, is a critical negative regulator of both the innate and adaptive immune response in mice, and its altered functions are likely to be involved in autoimmune diseases. Small molecules that modulate Sirt1 functions are potential therapeutic reagents for autoimmune inflammatory diseases. This review highlights the role of Sirt1 in immune regulation and RA.
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Affiliation(s)
- Sinyi Kong
- Department of Pathology, Northwestern University, Feinberg School of Medicine, 303 E Chicago Ave, Chicago, IL 60612, USA
| | - Pricilla Yeung
- Department of Pathology, Northwestern University, Feinberg School of Medicine, 303 E Chicago Ave, Chicago, IL 60612, USA
| | - Deyu Fang
- Department of Pathology, Northwestern University, Feinberg School of Medicine, 303 E Chicago Ave, Chicago, IL 60612, USA
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Synergistic effects of interleukin-1β and interleukin-17A antibodies on collagen-induced arthritis mouse model. Int Immunopharmacol 2013; 15:199-205. [DOI: 10.1016/j.intimp.2012.12.010] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2012] [Revised: 12/07/2012] [Accepted: 12/14/2012] [Indexed: 01/28/2023]
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Tyagi AM, Srivastava K, Mansoori MN, Trivedi R, Chattopadhyay N, Singh D. Estrogen deficiency induces the differentiation of IL-17 secreting Th17 cells: a new candidate in the pathogenesis of osteoporosis. PLoS One 2012; 7:e44552. [PMID: 22970248 PMCID: PMC3438183 DOI: 10.1371/journal.pone.0044552] [Citation(s) in RCA: 221] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2012] [Accepted: 08/06/2012] [Indexed: 01/05/2023] Open
Abstract
Th17 cells produce IL-17, and the latter promotes bone loss in collagen-induced arthritis in mice. Blocking IL-17 action in mouse model of rheumatoid arthritis reduces disease symptoms. These observations suggest that Th17 cells may be involved in the pathogenesis of bone loss. However, the role of Th17 cell in estrogen (E2) deficiency-induced bone loss is still not very clear. We investigated the effect of E2 on Th17 differentiation in vivo and IL-17 mediated regulation of osteoclast and osteoblast differentiation. Additionally, effect of IL-17 functional block under E2 deficiency-induced bone loss was studied. In murine bone marrow cells, E2 suppressed IL-17 mediated osteoclast differentiation. IL-17 inhibited formation of mineralized nodules in osteoblasts and this effect was suppressed by E2. E2 treatment to mouse calvarial osteoblasts inhibited the IL-17-induced production of osteoclastogenic cytokines and NF-kB translocation. In ovariectomized mice, there was increase in the number of Th17 cells, transcription factors promoting Th17 cell differentiation and circulating IL-17 levels. These effects were reversed by E2 supplementation. Treatment of neutralizing IL-17 monoclonal antibody to Ovx mice mitigated the E2 deficiency-induced trabecular bone loss and reversed the decreased osteoprotegerin-to-receptor activator of nuclear factor kappa B ligand (RANKL) transcript levels in long bones, increased osteoclast differentiation from the bone marrow precursor cells and decreased osteoblast differentiation from the bone marrow stromal cells. Our findings indicate that E2 deficiency leads to increased differentiation of Th17 cells with attendant up regulation of STAT3, ROR-γt and ROR-α and downregulation of Foxp3 which antagonizes Th17 cell differentiation. Increased IL-17 production in turn induces bone loss by increasing pro-osteoclastogenic cytokines including TNF-α, IL-6 and RANKL from osteoblasts and functional block of IL-17 prevents bone loss. IL-17 thus plays a critical causal role in Ovx-induced bone loss and may be considered a potential therapeutic target in pathogenesis of post menopausal osteoporosis.
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Affiliation(s)
- Abdul M. Tyagi
- Division of Endocrinology, Central Drug Research Institute (Council of Scientific and Industrial Research), Chattar Manzil, Lucknow, India
| | - Kamini Srivastava
- Division of Endocrinology, Central Drug Research Institute (Council of Scientific and Industrial Research), Chattar Manzil, Lucknow, India
| | - Mohd Nizam Mansoori
- Division of Endocrinology, Central Drug Research Institute (Council of Scientific and Industrial Research), Chattar Manzil, Lucknow, India
| | - Ritu Trivedi
- Division of Endocrinology, Central Drug Research Institute (Council of Scientific and Industrial Research), Chattar Manzil, Lucknow, India
| | - Naibedya Chattopadhyay
- Division of Endocrinology, Central Drug Research Institute (Council of Scientific and Industrial Research), Chattar Manzil, Lucknow, India
| | - Divya Singh
- Division of Endocrinology, Central Drug Research Institute (Council of Scientific and Industrial Research), Chattar Manzil, Lucknow, India
- * E-mail:
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Lin J, Zhou Z, Huo R, Xiao L, Ouyang G, Wang L, Sun Y, Shen B, Li D, Li N. Cyr61 Induces IL-6 Production by Fibroblast-like Synoviocytes Promoting Th17 Differentiation in Rheumatoid Arthritis. THE JOURNAL OF IMMUNOLOGY 2012; 188:5776-84. [DOI: 10.4049/jimmunol.1103201] [Citation(s) in RCA: 82] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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Biswas PS, Kang K, Gupta S, Bhagat G, Pernis AB. A murine autoimmune model of rheumatoid arthritis and systemic lupus erythematosus associated with deregulated production of IL-17 and IL-21. Methods Mol Biol 2012; 900:233-51. [PMID: 22933072 DOI: 10.1007/978-1-60761-720-4_11] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
T-helper cell 17 (Th17) cells play an important role in the pathogenesis of many autoimmune disorders including Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE). In this chapter we describe a murine model where deregulated production of IL-17 and IL-21 can lead to either lupus-like disease or RA-like symptoms depending on the genetic background. We delineate the key techniques that can be used to dissect the mechanisms responsible for the pathogenesis of these diseases at both a cellular and molecular level including in vitro Th17 cell differentiation, chromatin immunoprecipitation assays, and retroviral transduction experiments. We also describe the methodologies that can be utilized to monitor the classic clinical findings of RA and SLE in murine models. Given the broad involvement of deregulated production of IL-17 and IL-21 in autoimmunity, many of these techniques could also be valuable for the investigation of these pathways in murine models of other autoimmune diseases.
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Affiliation(s)
- Partha S Biswas
- Autoimmunity & Inflammation Program, Hospital for Special Surgery, New York, NY, USA
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Pickens SR, Chamberlain ND, Volin MV, Mandelin AM, Agrawal H, Matsui M, Yoshimoto T, Shahrara S. Local expression of interleukin-27 ameliorates collagen-induced arthritis. ARTHRITIS AND RHEUMATISM 2011; 63:2289-98. [PMID: 21384333 PMCID: PMC3115512 DOI: 10.1002/art.30324] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
OBJECTIVE To determine the mechanism of action of interleukin-27 (IL-27) against rheumatoid arthritis (RA). METHODS Adenovirus containing IL-27 transcript was constructed and was locally delivered into the ankles of mice with collagen-induced arthritis (CIA). Progression of arthritis was determined in treated and untreated mice by measuring ankle circumference and through histologic analysis. IL-17 and its downstream targets as well as cytokines promoting Th17 cell differentiation were quantified by enzyme-linked immunosorbent assay in CIA mouse ankles locally expressing adenoviral IL-27 as well as in control-treated mouse ankles. Ankles from both treatment groups were immunostained for neutrophil and monocyte migration (macrophages in the tissue). Finally, vascularization was quantified by histology and by determining ankle hemoglobin levels. RESULTS Ectopic expression of IL-27 in CIA mice ameliorated inflammation, lining hypertrophy, and bone erosion as compared with control-treated CIA mice. Serum and joint levels of IL-17 were significantly reduced in the IL-27-treated group compared with the control-treated group. Two of the main cytokines that induce Th17 cell differentiation and IL-17 downstream target molecules were greatly down-regulated in CIA mouse ankles receiving forced expression of IL-27. The control mice had higher levels of vascularization and monocyte trafficking than did mice ectopically expressing IL-27. CONCLUSION Our results suggest that increased levels of IL-27 relieve arthritis in CIA mouse ankles. This amelioration of arthritis involves a reduction in CIA mouse serum and joint levels of IL-17 and results in decreased IL-17-mediated monocyte recruitment and angiogenesis. Hence, the use of IL-27 may be a strategy for treatment of patients with RA.
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Affiliation(s)
- Sarah R. Pickens
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
| | - Nathan D. Chamberlain
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
| | - Michael V. Volin
- Department of Microbiology & Immunology, Midwestern University, Chicago College of Osteopathic Medicine, Downers Grove, IL 60515
| | - Arthur M. Mandelin
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
| | - Hemant Agrawal
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
| | - Masanori Matsui
- Department of Microbiology, Saitama Medical University, Japan
| | | | - Shiva Shahrara
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
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The Th17/Treg imbalance and cytokine environment in peripheral blood of patients with rheumatoid arthritis. Rheumatol Int 2011; 32:887-93. [DOI: 10.1007/s00296-010-1710-0] [Citation(s) in RCA: 148] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2010] [Accepted: 12/18/2010] [Indexed: 12/22/2022]
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Hsu YH, Chang MS. Interleukin-20 antibody is a potential therapeutic agent for experimental arthritis. ACTA ACUST UNITED AC 2010; 62:3311-21. [PMID: 20722035 DOI: 10.1002/art.27689] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
OBJECTIVE Interleukin-20 (IL-20) is a proinflammatory cytokine involved in the pathogenesis of rheumatoid arthritis (RA). We investigated whether anti-IL-20 antibody treatment would modulate the severity of the disease in a collagen-induced arthritis (CIA) rat model. METHODS We generated a CIA model by immunizing rats with bovine type II collagen. Rats with CIA were treated subcutaneously with anti-IL-20 antibody 7E, with the tumor necrosis factor (TNF) blocker etanercept, or with 7E in combination with etanercept. Arthritis severity was determined according to the hind paw thickness, arthritis severity score, degree of cartilage damage, bone mineral density, and cytokine production, which were evaluated using radiologic scans, microfocal computed tomography, and enzyme-linked immunosorbent assay. To analyze gene regulation by IL-20, rat synovial fibroblasts (SFs) were isolated and analyzed for the expression of RANKL, IL-17, and TNFα. We also used real-time quantitative polymerase chain reaction analysis and flow cytometry to determine IL-20-regulated RANKL in mouse osteoblastic MC3T3-E1 cells and Th17 cells. RESULTS In vivo, treatment with 7E alone or in combination with etanercept significantly reduced the severity of arthritis by decreasing the hind paw thickness and swelling, preventing cartilage damage and bone loss, and reducing the expression of IL-20, IL-1β, IL-6, RANKL, and matrix metalloproteinases (MMPs) in synovial tissue. In vitro, IL-20 induced TNFα expression in SFs from rats with CIA. IL-20 markedly induced RANKL production in SFs, osteoblasts, and Th17 cells. CONCLUSION Selectively blocking IL-20 inhibited inflammation and bone loss in rats with CIA. Treatment with 7E combined with etanercept protected rats from CIA better than treatment with etanercept alone. Our findings provide evidence that IL-20 is a novel target and that 7E may be a potential therapeutic agent for RA.
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40
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Cascão R, Moura RA, Perpétuo I, Canhão H, Vieira-Sousa E, Mourão AF, Rodrigues AM, Polido-Pereira J, Queiroz MV, Rosário HS, Souto-Carneiro MM, Graca L, Fonseca JE. Identification of a cytokine network sustaining neutrophil and Th17 activation in untreated early rheumatoid arthritis. Arthritis Res Ther 2010; 12:R196. [PMID: 20961415 PMCID: PMC2991033 DOI: 10.1186/ar3168] [Citation(s) in RCA: 94] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2010] [Revised: 09/09/2010] [Accepted: 10/20/2010] [Indexed: 02/06/2023] Open
Abstract
Introduction Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by sustained synovitis. Recently, several studies have proposed neutrophils and Th17 cells as key players in the onset and perpetuation of this disease. The main goal of this work was to determine whether cytokines driving neutrophil and Th17 activation are dysregulated in very early rheumatoid arthritis patients with less than 6 weeks of disease duration and before treatment (VERA). Methods Cytokines related to neutrophil and Th17 activation were quantified in the serum of VERA and established RA patients and compared with other very early arthritis (VEA) and healthy controls. Synovial fluid (SF) from RA and osteoarthritis (OA) patients was also analyzed. Results VERA patients had increased serum levels of cytokines promoting Th17 polarization (IL-1β and IL-6), as well as IL-8 and Th17-derived cytokines (IL-17A and IL-22) known to induce neutrophil-mediated inflammation. In established RA this pattern is more evident within the SF. Early treatment with methotrexate or corticosteroids led to clinical improvement but without an impact on the cytokine pattern. Conclusions VERA patients already display increased levels of cytokines related with Th17 polarization and neutrophil recruitment and activation, a dysregulation also found in SF of established RA. 0 Thus, our data suggest that a cytokine-milieu favoring Th17 and neutrophil activity is an early event in RA pathogenesis.
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Affiliation(s)
- Rita Cascão
- Rheumatology Research Unit, Instituto de Medicina Molecular, Edifício Egas Moniz, Faculdade de Medicina da Universidade de Lisboa, Av Professor Egas Moniz, Lisboa 1649-028, Portugal.
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41
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Batsalova T, Dzhambazov B, Klaczkowska D, Holmdahl R. Mice producing less reactive oxygen species are relatively resistant to collagen glycopeptide vaccination against arthritis. THE JOURNAL OF IMMUNOLOGY 2010; 185:2701-9. [PMID: 20686129 DOI: 10.4049/jimmunol.1000385] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The bottleneck for the induction of collagen-induced arthritis in mice is the recognition of immunodominant type II collagen (CII) peptide (CII259-273) bound to the MHC class II molecule A(q). We have shown previously that the posttranslationally glycosylated lysine at position 264 in this epitope is of great importance for T cell recognition and tolerance induction to CII as well as for arthritis development. The Ncf1 gene, controlling oxidative burst, has been shown to play an important role for immune tolerance to CII. To investigate the effect of oxidation on the efficiency of immune-specific vaccination with MHC class II/glycosylated-CII peptide complexes, we used Ncf1 mutated mice. We demonstrate that normal reactive oxygen species (ROS) levels contribute to the establishment of tolerance and arthritis protection, because only mice with a functional oxidative burst were completely protected from arthritis after administration of the glycosylated CII259-273 peptide in complex with MHC class II. Transfer of T cells from vaccinated mice with functional Ncf1 protein resulted in strong suppression of clinical signs of arthritis in B10.Q mice, whereas the Ncf1 mutated mice as recipients had a weaker suppressive effect, suggesting that ROS modified the secondary rather than the primary immune response. A milder but still significant effect was also observed in ROS deficient mice. During the primary vaccination response, regulatory T cells, upregulation of negative costimulatory molecules, and increased production of anti-inflammatory versus proinflammatory cytokines in both Ncf1 mutated and wild type B10.Q mice was observed, which could explain the vaccination effect independent of ROS.
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Affiliation(s)
- Tsvetelina Batsalova
- Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
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42
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Shahrara S, Pickens SR, Mandelin AM, Karpus WJ, Huang Q, Kolls JK, Pope RM. IL-17-mediated monocyte migration occurs partially through CC chemokine ligand 2/monocyte chemoattractant protein-1 induction. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2010; 184:4479-87. [PMID: 20228199 PMCID: PMC2858914 DOI: 10.4049/jimmunol.0901942] [Citation(s) in RCA: 121] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory disease that is mediated, in part, by proinflammatory factors produced by RA synovial tissue (ST) fibroblasts and macrophages, resulting in monocyte migration from the blood to the ST. To characterize the potential role of IL-17 in monocyte migration, RA synovial fibroblasts and macrophages were activated with IL-17 and examined for the expression of monocyte chemokines. The two potentially important monocyte chemoattractants identified were CCL20/MIP-3alpha and CCL2/MCP-1, which were significantly induced in RA synovial fibroblasts and macrophages. However, in vivo, only CCL2/MCP-1 was detectable following adenovirus IL-17 injection. We found that IL-17 induction of CCL2/MCP-1 was mediated by the PI3K, ERK, and JNK pathways in RA ST fibroblasts and by the PI3K and ERK pathways in macrophages. Further, we show that neutralization of CCL2/MCP-1 significantly reduced IL-17-mediated monocyte recruitment into the peritoneal cavity. We demonstrate that local expression of IL-17 in ankle joints was associated with significantly increased monocyte migration and CCL2/MCP-1 levels. Interestingly, we show that RA synovial fluids immunoneutralized for IL-17 and CCL2/MCP-1 have similar monocyte chemotaxis activity as those immunoneutralized for each factor alone. In short, CCL2/MCP-1 produced from cell types present in the RA joint, as well as in experimental arthritis, may be responsible, in part, for IL-17-induced monocyte migration; hence, these results suggest that CCL2/MCP-1 is a downstream target of IL-17 that may be important in RA.
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Affiliation(s)
- Shiva Shahrara
- Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
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43
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Pickens SR, Volin MV, Mandelin AM, Kolls JK, Pope RM, Shahrara S. IL-17 contributes to angiogenesis in rheumatoid arthritis. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2010; 184:3233-41. [PMID: 20173024 PMCID: PMC2857761 DOI: 10.4049/jimmunol.0903271] [Citation(s) in RCA: 150] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Angiogenesis is an early and a critical event in the pathogenesis of rheumatoid arthritis (RA). Neovascularization is dependent on endothelial cell activation, migration and proliferation, and inhibition of angiogenesis may provide a novel therapeutic approach in RA. In this study, we document a novel role of IL-17 in mediating angiogenesis. Local expression of IL-17 in mouse ankles increases vascularity. We further demonstrate that IL-17 is angiogenic by showing its ability to promote blood vessel growth in Matrigel plugs in vivo. Additionally, IL-17, in concentrations present in the RA joint, induces human lung microvascular endothelial cell (HMVEC) migration mediated through the PI3K/AKT1 pathway. Furthermore, suppression of the PI3K pathway markedly reduces IL-17-induced tube formation. We also show that both IL-17-induced HMVEC chemotaxis and tube formation are mediated primarily through IL-17 receptor C. Neutralization of either IL-17 in RA synovial fluids or IL-17 receptor C on HMVECs significantly reduces the induction of HMVEC migration by RA synovial fluid. Finally, RA synovial fluid immunoneutralized with anti-IL-17 and antivascular endothelial growth factor does not reduce HMVEC migration beyond the effect detected by immunodepleting each factor alone. These observations identify a novel function for IL-17 as an angiogenic mediator in RA, supporting IL-17 as a therapeutic target in RA.
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MESH Headings
- Angiogenic Proteins/antagonists & inhibitors
- Angiogenic Proteins/biosynthesis
- Angiogenic Proteins/physiology
- Animals
- Ankle Joint/blood supply
- Ankle Joint/immunology
- Ankle Joint/pathology
- Arthritis, Experimental/immunology
- Arthritis, Experimental/pathology
- Arthritis, Experimental/physiopathology
- Arthritis, Rheumatoid/immunology
- Arthritis, Rheumatoid/pathology
- Arthritis, Rheumatoid/physiopathology
- Cell Line
- Cell Migration Inhibition/immunology
- Cell Movement/immunology
- Cells, Cultured
- Endothelium, Vascular/cytology
- Endothelium, Vascular/immunology
- Endothelium, Vascular/metabolism
- Humans
- Inflammation Mediators/antagonists & inhibitors
- Inflammation Mediators/metabolism
- Inflammation Mediators/physiology
- Interleukin-17/antagonists & inhibitors
- Interleukin-17/biosynthesis
- Interleukin-17/physiology
- Lung/blood supply
- Lung/immunology
- Lung/metabolism
- Mice
- Mice, Inbred C57BL
- Receptors, Interleukin-17/physiology
- Synovial Fluid/cytology
- Synovial Fluid/immunology
- Vascular Endothelial Growth Factor A/antagonists & inhibitors
- Vascular Endothelial Growth Factor A/physiology
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Affiliation(s)
- Sarah R. Pickens
- Department of Medicine, Feinberg School of Medicine, Northwestern University Chicago, IL 60611
| | - Michael V. Volin
- Department of Microbiology & Immunology, Midwestern University, Chicago College of Osteopathic Medicine, Downers Grove, IL 60515
| | - Arthur M. Mandelin
- Department of Medicine, Feinberg School of Medicine, Northwestern University Chicago, IL 60611
| | - Jay K. Kolls
- LSU Health Sciences Center Department of Genetics New Orleans, LA 70112
| | - Richard M. Pope
- Department of Medicine, Feinberg School of Medicine, Northwestern University Chicago, IL 60611
- Jesse Brown VA Chicago Healthcare System, Chicago, IL 60611
| | - Shiva Shahrara
- Department of Medicine, Feinberg School of Medicine, Northwestern University Chicago, IL 60611
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44
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Jiao Z, Wang W, Guo M, Zhang T, Chen L, Wang Y, You H, Li J. Expression analysis of Notch-related molecules in peripheral blood T helper cells of patients with rheumatoid arthritis. Scand J Rheumatol 2010; 39:26-32. [PMID: 20132067 DOI: 10.3109/03009740903124424] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
OBJECTIVE Expression of Notch homologues in local tissue inflammation in rheumatoid arthritis (RA) and cultured synoviocytes has been reported, but the expression profile of Notch-related molecules in peripheral lymphocytes in RA remains unclear. In this study, we measured the expression of Notch receptors and downstream molecules in peripheral lymphocytes from RA patients. METHODS Expression of Notch receptors in peripheral lymphocytes of RA patients was assessed by both flow cytometry and real-time polymerase chain reaction (PCR). Expression of the representative Notch target gene HES-1 and the regulatory gene NUMB in purified T helper cells from RA patients was determined by real-time PCR, and expression of Notch intracellular domain (ICD) was determined by immunoblot analysis. RESULTS There was an increased expression of Notch 2, Notch 3, and Notch 4 in T helper cells from active RA patients, among which increased expression of Notch 3 was mainly by activated T cells. Notably, expression of Notch 3 in T cells decreased in inactive RA patients and the level was similar to that of healthy controls (HC). Notch receptors were rarely observed on B cells and no difference in expression was found between RA patients and HC. T helper cells from RA patients exhibited increased expression of the target gene HES-1 but decreased expression of the negative modulation gene NUMB of Notch signalling. There was also an increased nuclear translocation of Notch-ICD in T helper cells from active RA disease. CONCLUSION The present study demonstrated that T helper cells from RA patients display a significantly altered expression profile of Notch receptors and enhanced activation of Notch signalling compared with HC.
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Affiliation(s)
- Z Jiao
- Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, PR China.
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45
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Baek SA, Hahn WH, Cho BS, Kim SD. Association between polymorphisms in Interleukin-17 receptor A gene and childhood IgA nephropathy. KOREAN JOURNAL OF PEDIATRICS 2010. [DOI: 10.3345/kjp.2010.53.2.215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Affiliation(s)
- Seung-Ah Baek
- Department of Pediatrics, School of Medicine, Kyung Hee University, Seoul, Korea
| | - Won-Ho Hahn
- Department of Pediatrics, School of Medicine, Kyung Hee University, Seoul, Korea
| | - Byoung-Soo Cho
- Department of Pediatrics, School of Medicine, Kyung Hee University, Seoul, Korea
- East West Kidney Diseases Research Institute, Kyung Hee University, Seoul, Korea
| | - Sung-Do Kim
- Department of Pediatrics, School of Medicine, Kyung Hee University, Seoul, Korea
- East West Kidney Diseases Research Institute, Kyung Hee University, Seoul, Korea
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46
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Zhang J, Wang X, Fahmi H, Wojcik S, Fikes J, Yu Y, Wu J, Luo H. Role of TL1A in the pathogenesis of rheumatoid arthritis. THE JOURNAL OF IMMUNOLOGY 2009; 183:5350-7. [PMID: 19786547 DOI: 10.4049/jimmunol.0802645] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
TNF-like ligand 1A (TL1A), a member of the TNF superfamily, is the ligand of DR3 and DcR3. Several types of cells, such as endothelial cells, monocytes/macrophages, dendritic cells, and CD4 and CD8 T cells, are capable of producing this cytokine. In present study, we demonstrated that TL1A aggravated collagen-induced arthritis in mice. It increased collagen-induced arthritis penetrance and clinical scores as well as the severity of the pathological findings. TL1A administration led to the occurrence of multiple enlarged germinal centers in the spleen, and it boosted serum anti-collagen Ab titers in vivo. In vitro, TL1A augmented TNF-alpha production by T cells upon TCR ligation, and it greatly enhanced Th17 differentiation and IL-17 production. We further showed that human rheumatoid arthritis (RA) synovial fluids had elevated TL1A titers, and human chrondrocytes and synovial fibroblasts were capable of secreting TL1A upon TNF-alpha or IL-1beta stimulation. Taken together, these data suggest that TL1A secretion in lymphoid organs might contribute to RA initiation by promoting autoantibody production, and TL1A secretion stimulated by inflammatory cytokines in RA joints might be a part of a vicious circle that aggravates RA pathogenesis.
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Affiliation(s)
- Jun Zhang
- Research Center, Entre Hospitalier de l'Université de Montréal, Notre-Dame Hospital, Montreal, Quebec, Canada
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47
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Abstract
Recent work has implicated a novel Th effector cell subset, the Th17 cell subset, in the development of both rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) because of the ability of Th17 cells to produce cytokines like IL-17 and IL-21 that can drive both inflammatory and humoral responses. In this review, we will discuss recent studies that have begun elucidating the factors that regulate the development of Th17 cells and provide a brief overview of the role of Th17 cells in RA and SLE.
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Affiliation(s)
- A B Pernis
- Department of Medicine, Columbia University, New York, NY 10032, USA.
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48
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Shahrara S, Pickens SR, Dorfleutner A, Pope RM. IL-17 induces monocyte migration in rheumatoid arthritis. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2009; 182:3884-91. [PMID: 19265168 PMCID: PMC2811490 DOI: 10.4049/jimmunol.0802246] [Citation(s) in RCA: 145] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease which is in part mediated by the migration of monocytes from blood to RA synovial tissue, where they differentiate into macrophages and secrete inflammatory cytokines and chemokines. The T cell cytokine IL-17 is expressed in the RA synovial tissue and synovial fluid. To better understand the mechanism by which IL-17 might promote inflammation, its role in monocyte trafficking was examined. In vivo, IL-17 mediates monocyte migration into sponges implanted into SCID mice. In vitro, IL-17 was chemotactic, not chemokinetic, for monocytes at the concentrations detected in the RA synovial fluid. Further, IL-17-induced monocyte migration was mediated by ligation to IL-17RA and RC expressed on monocytes and was mediated through p38MAPK signaling. Finally, neutralization of IL-17 in RA synovial fluid or its receptors on monocytes significantly reduced monocyte migration mediated by RA synovial fluid. These observations suggest that IL-17 may be important in recruiting monocytes into the joints of patients with RA, supporting IL-17 as a therapeutic target in RA.
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Affiliation(s)
- Shiva Shahrara
- Department of Medicine, Feinberg School of Medicine, Northwestern University Chicago, IL 60611, USA.
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49
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Egan PJ, van Nieuwenhuijze A, Campbell IK, Wicks IP. Promotion of the local differentiation of murine Th17 cells by synovial macrophages during acute inflammatory arthritis. ACTA ACUST UNITED AC 2009; 58:3720-9. [PMID: 19035489 DOI: 10.1002/art.24075] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
OBJECTIVE To examine the generation of proinflammatory Th17 cells at the site of tissue inflammation and in draining lymph nodes using an interleukin-17 (IL-17)-dependent model of acute inflammatory arthritis. METHODS Arthritis was elicited in mice by intraarticular injection of methylated bovine serum albumin (mBSA) into the knee and subcutaneous injection of IL-1beta. Anti-IL-17 or control antibodies were administered during arthritis induction. Cytokine expression was evaluated by intracellular cytokine staining of synovial lymphocytes, by polymerase chain reaction analysis of RNA extracted from lymph node cells, and by enzyme-linked immunosorbent assay of cell culture supernatants. Th17 differentiation of naive CD4+ T cells was assessed in cocultures with macrophages from arthritic mice. RESULTS Anti-IL-17 antibody administered during acute arthritis markedly reduced disease, indicating that the model is IL-17 dependent. IL-17 messenger RNA (mRNA), but not protein, was detected in draining lymph node CD4+ T cells and preceded joint inflammation. In addition, mRNA for Th17 cell-stimulatory cytokines (transforming growth factor beta, IL-6) and Th17 cell-inhibitory cytokines (interferon-gamma, IL-4) was detected in lymph nodes following injection of mBSA and IL-1beta. Th17 cells were clearly identified in the inflamed synovium at the peak of disease. Synovial macrophages supported Th17 cell generation from naive CD4+ T cell precursors stimulated via CD3 in vitro and produced high levels of IL-6. In contrast, peritoneal macrophages failed to induce Th17 cell differentiation and produced less IL-6. CONCLUSION These results suggest that Th17 cell differentiation is initiated in draining lymph nodes but that IL-17-producing cells are restricted to the inflamed synovium, being generated in response to local cytokines produced by inflammatory macrophages.
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Affiliation(s)
- Paul J Egan
- Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
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50
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Chen Q, Yang W, Gupta S, Biswas P, Smith P, Bhagat G, Pernis AB. IRF-4-binding protein inhibits interleukin-17 and interleukin-21 production by controlling the activity of IRF-4 transcription factor. Immunity 2008; 29:899-911. [PMID: 19062315 PMCID: PMC2633410 DOI: 10.1016/j.immuni.2008.10.011] [Citation(s) in RCA: 154] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2008] [Revised: 09/04/2008] [Accepted: 10/07/2008] [Indexed: 01/09/2023]
Abstract
The T helper 17 (Th17) cell lineage is important in inflammatory and autoimmune responses, via its ability to produce interleukin-17 (IL-17) and IL-21. Given the potentially deleterious effects of Th17 cells, their generation needs to be strictly controlled. IRF-4 is a transcription factor that has recently emerged as a key regulator of Th17 cell differentiation. Here, we showed that mice deficient in a previously isolated protein, IBP (IRF-4-binding protein), rapidly developed rheumatoid arthritis-like joint disease and large-vessel vasculitis. The pathology was associated with an enhanced responsiveness of T cells to low levels of stimulation and with the inappropriate synthesis of IL-17 and IL-21. IBP sequestered IRF-4 and prevented it from targeting the transcriptional regulatory regions of the genes that encode IL-17 and IL-21. Thus, IBP appears to be important in preventing T cell-mediated autoimmunity by ensuring that the production of IL-17 and IL-21 does not occur in response to self-antigens.
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MESH Headings
- Animals
- Arthritis, Rheumatoid/genetics
- Arthritis, Rheumatoid/immunology
- Arthritis, Rheumatoid/metabolism
- Arthritis, Rheumatoid/pathology
- Cytokines/immunology
- Cytokines/metabolism
- DNA-Binding Proteins/genetics
- DNA-Binding Proteins/metabolism
- Female
- Guanine Nucleotide Exchange Factors
- Interferon Regulatory Factors/metabolism
- Interleukin-17/antagonists & inhibitors
- Interleukin-17/genetics
- Interleukins/antagonists & inhibitors
- Interleukins/genetics
- Mice
- Mice, Mutant Strains
- Nuclear Proteins/genetics
- Nuclear Proteins/metabolism
- Promoter Regions, Genetic/immunology
- Receptors, Antigen, T-Cell/immunology
- Receptors, Antigen, T-Cell/metabolism
- T-Lymphocytes, Helper-Inducer/immunology
- Vasculitis/genetics
- Vasculitis/immunology
- Vasculitis/pathology
- Interleukin-21
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Affiliation(s)
- Qinzhong Chen
- Department of Medicine, Columbia University, New York, NY 10032, USA
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