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Barker KH, Higham JP, Pattison LA, Chessell IP, Welsh F, Smith ESJ, Bulmer DC. Sensitization of colonic nociceptors by IL-13 is dependent on JAK and p38 MAPK activity. Am J Physiol Gastrointest Liver Physiol 2023; 324:G250-G261. [PMID: 36749569 PMCID: PMC10010921 DOI: 10.1152/ajpgi.00280.2022] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The effective management of visceral pain is a significant unmet clinical need for those affected by gastrointestinal diseases, such as inflammatory bowel disease (IBD). The rational design of novel analgesics requires a greater understanding of the mediators and mechanisms underpinning visceral pain. Interleukin-13 (IL-13) production by immune cells residing in the gut is elevated in IBD, and IL-13 appears to be important in the development of experimental colitis. Furthermore, receptors for IL-13 are expressed by neurons innervating the colon, though it is not known whether IL-13 plays any role in visceral nociception per se. To resolve this, we used Ca2+ imaging of cultured sensory neurons and ex vivo electrophysiological recording from the lumbar splanchnic nerve innervating the distal colon. Ca2+ imaging revealed the stimulation of small-diameter, capsaicin-sensitive sensory neurons by IL-13, indicating that IL-13 likely stimulates nociceptors. IL-13-evoked Ca2+ signals were attenuated by inhibition of Janus (JAK) and p38 kinases. In the lumbar splanchnic nerve, IL-13 did not elevate baseline firing, nor sensitize the response to capsaicin application, but did enhance the response to distention of the colon. In line with Ca2+ imaging experiments, IL-13-mediated sensitization of the afferent response to colon distention was blocked by inhibition of either JAK or p38 kinase signaling. Together, these data highlight a potential role for IL-13 in visceral nociception and implicate JAK and p38 kinases in pronociceptive signaling downstream of IL-13.
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Affiliation(s)
- Katie H Barker
- Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom
| | - James P Higham
- Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom
| | - Luke A Pattison
- Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom
| | - Iain P Chessell
- Department of Neuroscience, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
| | - Fraser Welsh
- Department of Neuroscience, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
| | - Ewan St J Smith
- Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom
| | - David C Bulmer
- Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom
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2
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Giuffrida P, Caprioli F, Facciotti F, Di Sabatino A. The role of interleukin-13 in chronic inflammatory intestinal disorders. Autoimmun Rev 2019; 18:549-555. [DOI: 10.1016/j.autrev.2019.03.012] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2018] [Accepted: 01/04/2019] [Indexed: 12/17/2022]
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3
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Inhibition of IL-13 and IL-13Rα2 Expression by IL-32θ in Human Monocytic Cells Requires PKCδ and STAT3 Association. Int J Mol Sci 2019; 20:ijms20081949. [PMID: 31010051 PMCID: PMC6514684 DOI: 10.3390/ijms20081949] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2019] [Revised: 04/06/2019] [Accepted: 04/19/2019] [Indexed: 12/27/2022] Open
Abstract
Interleukin (IL)-32θ, a newly identified IL-32 isoform, has been reported to exert pro-inflammatory effects through the association with protein kinase C delta (PKCδ). In this study, we further examined the effects of IL-32θ on IL-13 and IL-13Rα2 expression and the related mechanism in THP-1 cells. Upon stimulating IL-32θ-expressing and non-expressing cells with phorbol 12-myristate 13-acetate (PMA), the previous microarray analysis showed that IL-13Rα2 and IL-13 mRNA expression were significantly decreased by IL-32θ. The protein expression of these factors was also confirmed to be down-regulated. The nuclear translocation of transcription factors STAT3 and STAT6, which are necessary for IL-13Rα2 and IL-13 promoter activities, was suppressed by IL-32θ. Additionally, a direct association was found between IL-32θ, PKCδ, and signal transducer and activator of transcription 3 (STAT3), but not STAT6, revealing that IL-32θ might act mainly through STAT3 and indirectly affect STAT6. Moreover, the interaction of IL-32θ with STAT3 requires PKCδ, since blocking PKCδ activity eliminated the interaction and consequently limited the inhibitory effect of IL-32θ on STAT3 activity. Interfering with STAT3 or STAT6 binding by decoy oligodeoxynucleotides (ODNs) identified that IL-32θ had additive effects with the STAT3 decoy ODN to suppress IL-13 and IL-13Rα2 mRNA expression. Taken together, our data demonstrate the intracellular interaction of IL-32θ, PKCδ, and STAT3 to regulate IL-13 and IL-13Rα2 synthesis, supporting the role of IL-32θ as an inflammatory modulator.
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Mao YM, Zhao CN, Leng J, Leng RX, Ye DQ, Zheng SG, Pan HF. Interleukin-13: A promising therapeutic target for autoimmune disease. Cytokine Growth Factor Rev 2018; 45:9-23. [PMID: 30581068 DOI: 10.1016/j.cytogfr.2018.12.001] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Accepted: 12/11/2018] [Indexed: 12/16/2022]
Abstract
Interleukin-13 (IL-13) was previously thought to be a redundant presence of IL-4, but in recent years its role in immunity, inflammation, fibrosis, and allergic diseases has become increasingly prominent. IL-13 can regulate several subtypes of T helper (Th) cells and affect their transformation, including Th1, Th2, T17, etc., thus it may play an important role in immune system. Previous studies have revealed that IL-13 is implicated in the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), ulcerative colitis (UC), type 1 diabetes (T1D), sjogren's syndrome (SS), etc. In this review, we will briefly discuss the biological features of IL-13 and summarize recent advances in the role of IL-13 in the development and pathogenesis of autoimmune diseases. This information may provide new perspectives and suggestions for the selection of therapeutic targets for autoimmune diseases.
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Affiliation(s)
- Yan-Mei Mao
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Anhui Province Key Laboratory of Major Autoimmune Diseases, Hefei, Anhui, 230032, China
| | - Chan-Na Zhao
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Anhui Province Key Laboratory of Major Autoimmune Diseases, Hefei, Anhui, 230032, China
| | - Jing Leng
- Anhui Academy of Medical Sciences, 15 Yonghong Road, Hefei, Anhui, China
| | - Rui-Xue Leng
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Anhui Province Key Laboratory of Major Autoimmune Diseases, Hefei, Anhui, 230032, China
| | - Dong-Qing Ye
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Anhui Province Key Laboratory of Major Autoimmune Diseases, Hefei, Anhui, 230032, China
| | - Song Guo Zheng
- Division of Rheumatology, Penn State College of Medicine, Hershey, PA 17033, USA.
| | - Hai-Feng Pan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Anhui Province Key Laboratory of Major Autoimmune Diseases, Hefei, Anhui, 230032, China.
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5
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Yang SJ, Allahverdian S, Saunders ADR, Liu E, Dorscheid DR. IL-13 signaling through IL-13 receptor α2 mediates airway epithelial wound repair. FASEB J 2018; 33:3746-3757. [PMID: 30481486 DOI: 10.1096/fj.201801285r] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Asthma is an airway inflammatory disease characterized by epithelial barrier dysfunction and airway remodeling. Interleukin-13 (IL-13) is a pleiotropic cytokine shown to contribute to features of airway remodeling. We have previously demonstrated that IL-13 is an important mediator of normal airway epithelial repair and health. The role of IL-13 signaling via its receptor subunits (IL-13Rα1/IL-4Rα and IL-13Rα2) in airway epithelial repair and restoration of intact barrier function is not well understood and was investigated in this study using in vitro models. The blocking of IL-13 signaling via IL-13Rα2 significantly reduced airway epithelial repair by 24 h post-mechanical wounding in 1HAEo- cells. Expression and release of repair-mediating growth factor, heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF), and subsequent activation of EGF receptor (EGFR) were also significantly reduced in response to wounding when IL-13Rα2 was blocked. Our data support that IL-13 signals via IL-13Rα2 to mediate normal airway epithelial repair via HB-EGF-dependent activation of EGFR. In human donor lung tissues, we observed that airway epithelium of asthmatics expressed significantly decreased levels of IL-13Rα2 and increased levels of IL-13Rα1 compared with nonasthmatics. Dysregulated expression of IL-13 receptor subunits in the airways of asthmatics may thus contribute to the epithelial barrier dysfunction observed in asthma.-Yang, S. J., Allahverdian, S., Saunders, A. D. R., Liu, E., Dorscheid, D. R. IL-13 signaling through IL-13 receptor α2 mediates airway epithelial wound repair.
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Affiliation(s)
- S Jasemine Yang
- Department of Medicine, Centre for Heart Lung Innovation, Providence Health Care, University of British Columbia, Vancouver, British Columbia, Canada
| | - Sima Allahverdian
- Department of Medicine, Centre for Heart Lung Innovation, Providence Health Care, University of British Columbia, Vancouver, British Columbia, Canada
| | - Angela D R Saunders
- Department of Medicine, Centre for Heart Lung Innovation, Providence Health Care, University of British Columbia, Vancouver, British Columbia, Canada
| | - Emily Liu
- Department of Medicine, Centre for Heart Lung Innovation, Providence Health Care, University of British Columbia, Vancouver, British Columbia, Canada
| | - Delbert R Dorscheid
- Department of Medicine, Centre for Heart Lung Innovation, Providence Health Care, University of British Columbia, Vancouver, British Columbia, Canada
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Zhang Y, Li C, Zhang M, Li Z. IL-13 and IL-13Rα1 are overexpressed in extranodal natural killer/T cell lymphoma and mediate tumor cell proliferation. Biochem Biophys Res Commun 2018; 503:2715-2720. [PMID: 30107911 DOI: 10.1016/j.bbrc.2018.08.030] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Accepted: 08/03/2018] [Indexed: 02/06/2023]
Abstract
Extranodal NK/T cell lymphoma (NKTCL) is a rare but aggressive subtype of non-Hodgkin lymphoma. Multi-agent chemotherapy and involved-field radiotherapy are used to treat this disease, but the prognosis remains poor. Interleukin 13 and its receptors (IL-13Rs) are correlated with the pathogenesis and progression of various malignances. However, their roles in NKTCL have not been evaluated. In this study, we examined the roles of IL-13 and IL-13Rs in NKTCL and the underlying mechanisms. We found significantly higher serum IL-13 levels (p < 0.001) and IL-13Rα1 expression in tumor tissues (36 of 40, p < 0.001) in patients with NKTCL than in control cohort. IL-13 secretion was observed in tumor tissues (30 of 40, p < 0.001) and several cell lines of NKTCL. However, we did not detect significant associations between clinical characteristics and the expression levels of IL-13 or IL-13Rs. In vitro, IL-13 activated Stat6 and promoted cell proliferation in a dose-dependent manner. In addition, blocking IL-13 exerted a negative effect on tumor cell growth. We conclude that IL-13 functions as an autocrine growth factor in NKTCL and contributes to its pathogenesis. Blocking IL-13 is thus a potential therapeutic approach for NKTCL.
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Affiliation(s)
- Yanjie Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People's Republic of China
| | - Chaoping Li
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People's Republic of China
| | - Mingzhi Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People's Republic of China.
| | - Zhaoming Li
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People's Republic of China.
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7
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Lin C, Liu H, Zhang H, He H, Li H, Shen Z, Qin J, Qin X, Xu J, Sun Y. Interleukin-13 receptor α2 is associated with poor prognosis in patients with gastric cancer after gastrectomy. Oncotarget 2018; 7:49281-49288. [PMID: 27351230 PMCID: PMC5226507 DOI: 10.18632/oncotarget.10297] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Accepted: 06/13/2016] [Indexed: 12/23/2022] Open
Abstract
Background Interleukin-13 receptor α2 (IL-13Rα2) plays a vital role in the invasion and metastasis of various types of cancer, but its role in prognosis of patients with gastric cancer remains unknown. The aim of this study was to investigate the impact of IL-13Rα2 expression on the prognostic value in gastric cancer patients after surgery. Results Increased expression of IL-13Rα2 in tumoral tissue was associated with decreased overall survival rate (P < 0.001). IL-13Rα2 expression was an independent prognostic indicator for gastric cancer (P < 0.001). Stratification analyses showed IL-13Rα2 expression could give some additional prognostic information in tumors of different stages, especially in advanced tumors. Integrating IL-13Rα2 expression with generated a better nomogram that was validated by the validation set to predict the 5-year overall survival. Methods IL-13Rα2 expression was evaluated by tissue microarrays from 507 gastric cancer patients from two academic medical centers and statistically assessed for correlations with the clinical profiles and the prognosis of the patients with gastric cancer. The prognostic nomogram was designed to predict 5-year overall survival probability. Conclusions IL-13Rα2 expression might be an independent prognostic factor for gastric cancer after surgical resection and could potentially be a high-priority therapeutic target. Incorporating IL-13Rα2 expression into the TNM staging system can provide a good prognostic model.
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Affiliation(s)
- Chao Lin
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Hao Liu
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Heng Zhang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Hongyong He
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - He Li
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhenbin Shen
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jin Qin
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xinyu Qin
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jiejie Xu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Yihong Sun
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
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8
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Becerra-Díaz M, Wills-Karp M, Heller NM. New perspectives on the regulation of type II inflammation in asthma. F1000Res 2017; 6:1014. [PMID: 28721208 PMCID: PMC5497827 DOI: 10.12688/f1000research.11198.1] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/16/2017] [Indexed: 12/12/2022] Open
Abstract
Asthma is a chronic inflammatory disease of the lungs which has been thought to arise as a result of inappropriately directed T helper type-2 (Th2) immune responses of the lungs to otherwise innocuous inhaled antigens. Current asthma therapeutics are directed towards the amelioration of downstream consequences of type-2 immune responses (i.e. β-agonists) or broad-spectrum immunosuppression (i.e. corticosteroids). However, few approaches to date have been focused on the primary prevention of immune deviation. Advances in molecular phenotyping reveal heterogeneity within the asthmatic population with multiple endotypes whose varying expression depends on the interplay between numerous environmental factors and the inheritance of a broad range of susceptibility genes. The most common endotype is one described as "type-2-high" (i.e. high levels of interleukin [IL]-13, eosinophilia, and periostin). The identification of multiple endotypes has provided a potential explanation for the observations that therapies directed at typical Th2 cytokines (IL-4, IL-5, and IL-13) and their receptors have often fallen short when they were tested in a diverse group of asthmatic patients without first stratifying based on disease endotype or severity. However, despite the incorporation of endotype-dependent stratification schemes into clinical trial designs, variation in drug responses are still apparent, suggesting that additional genetic/environmental factors may be contributing to the diversity in drug efficacy. Herein, we will review recent advances in our understanding of the complex pathways involved in the initiation and regulation of type-2-mediated immune responses and their modulation by host factors (genetics, metabolic status, and the microbiome). Particular consideration will be given to how this knowledge could pave the way for further refinement of disease endotypes and/or the development of novel therapeutic strategies for the treatment of asthma .
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Affiliation(s)
- Mireya Becerra-Díaz
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Marsha Wills-Karp
- Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA
| | - Nicola M. Heller
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
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9
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IL-13 Signals Independent of IL-4 Receptor-Alpha Chain to Drive Ovalbumin-Induced Dermatitis. J Invest Dermatol 2016; 136:1286-1290. [DOI: 10.1016/j.jid.2015.11.033] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Revised: 10/23/2015] [Accepted: 11/09/2015] [Indexed: 11/19/2022]
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10
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Targeting the JAK-STAT pathway in the treatment of 'Th2-high' severe asthma. Future Med Chem 2016; 8:405-19. [PMID: 26934038 DOI: 10.4155/fmc.16.4] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Severe asthma is a heterogeneous disease characterized by reversible airway obstruction, chronic inflammation and airway remodeling. Phenotyping and/or endotyping can lead to a more personalized treatment strategy, improving the efficacy of novel drugs. Atopic asthma is associated with high levels of Th2 cells, implicated in a number of inflammatory responses. Differentiation of these cells from naive T cells occurs primarily via the JAK-STAT signaling pathway. Targeting this pathway through inhibition of activating cytokines (IL-4 and IL-13) and their receptors, the JAKs or the STATs, has been shown to have a therapeutic effect on asthma pathology. There are a number of novel drugs currently in development, which target various pathway components; these include both biologics and small molecules at various stages of development.
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11
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Jiang L, Cheng Q, Zhang B, Zhang M. IL-13 induces the expression of 11βHSD2 in IL-13Rα2 dependent manner and promotes the malignancy of colorectal cancer. Am J Transl Res 2016; 8:1064-1072. [PMID: 27158392 PMCID: PMC4846949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Accepted: 01/19/2016] [Indexed: 06/05/2023]
Abstract
Previous studies had demonstrated that IL-13 and its receptor IL-13Rα2 participated in the process of onset and development of colorectal cancer, however, its detailed mechanism was still unclear. Herein, we demonstrated that IL-13 induced the expression of 11βHSD2 in an IL-13Rα2 dependent manner in colorectal cancer cells. Furthermore, we indicated 11βHSD2 was critical for IL-13 to induce the expression of COX2 and activated Akt, which was essential for IL-13 to promote the colony formation abilities and migration abilities of colorectal cancer cells. Inhibitor of 11βHSD2 glycyrrhizic acid (GA) significantly reduced the liver metastasis of colorectal cancers cells seeded in the Appendix serous of the nude mice. These results provide evidences to reveal the molecular mechanism in the process of colorectal cancer involving IL-13 and its receptor IL-13Rα2, and may provide new therapeutic target for treatment of colorectal cancer.
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Affiliation(s)
- Li Jiang
- Department of Biliary and Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan 430030, China
| | - Qi Cheng
- Hepatic Surgery Center, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan 430030, China
| | - Binhao Zhang
- Hepatic Surgery Center, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan 430030, China
| | - Mingzhi Zhang
- Department of Medicine and Cancer Biology, Vanderbilt University School of MedicineNashville, Tennessee
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12
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Dames P, Bergann T, Fromm A, Bücker R, Barmeyer C, Krug SM, Fromm M, Schulzke JD. Interleukin-13 affects the epithelial sodium channel in the intestine by coordinated modulation of STAT6 and p38 MAPK activity. J Physiol 2015; 593:5269-82. [PMID: 26365358 DOI: 10.1113/jp271156] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Accepted: 08/28/2015] [Indexed: 12/13/2022] Open
Abstract
KEY POINTS Interleukin-13 (IL-13) causes intestinal epithelial barrier dysfunction, and is implicated in the pathogenesis of Th2-driven intestinal inflammation (e.g. ulcerative colitis). However, it is unclear whether the epithelial sodium channel (ENaC) - the main limiting factor for sodium absorption in the distal colon - is also influenced by IL-13 and if so, by what mechanism(s). We demonstrate in an intestinal cell model as well as in mouse distal colon that IL-13 causes reduced ENaC activity. We show that IL-13 impairs ENaC-dependent sodium transport by activating the JAK1/2-STAT6 signalling pathway. These results improve our understanding of the mechanisms through which IL-13 functions as a key effector cytokine in ulcerative colitis, thereby contributing to the distinct pathology of this disease. ABSTRACT Interleukin-13 (IL-13) has been strongly implicated in the pathogenesis of ulcerative colitis, possibly by disrupting epithelial integrity. In the distal colon, the epithelial sodium channel (ENaC) is an important factor in the regulation of sodium absorption, and therefore plays a critical role in minimizing intestinal sodium and water losses. In the present study, we investigated whether IL-13 also acts as a potent modulator of epithelial sodium transport via ENaC, and the signalling components involved. The effect of IL-13 on ENaC was examined in HT-29/B6-GR/MR human colon cells, as well as in mouse distal colon, by measuring amiloride-sensitive short-circuit current (ISC ) in Ussing chambers. The expression levels of ENaC subunits and the cellular components that contribute to ENaC activity were analysed by qRT-PCR and promoter gene assay. We show that IL-13, in both the cell model and in native intestinal tissue, impaired epithelial sodium absorption via ENaC (JNa ) as a result of decreased transcription levels of β- and γ-ENaC subunits and SGK1, a post-translational regulator of ENaC activity, due to impaired promoter activity. The reduction in JNa was prevented by inhibition of JAK1/2-STAT6 signalling. This inhibition also affected the IL-13-induced decrease in p38 MAPK phosphorylation. The contribution of STAT6 to IL-13-mediated ENaC inactivation was confirmed in a STAT6(-/-) mouse model. In conclusion, these results indicate that IL-13, the levels of which are elevated in ulcerative colitis, contributes to impaired ENaC activity via modulation of the STAT6/p38 MAPK pathways.
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Affiliation(s)
- Petra Dames
- Institute of Clinical Physiology, Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
| | - Theresa Bergann
- Institute of Clinical Physiology, Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
| | - Anja Fromm
- Institute of Clinical Physiology, Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
| | - Roland Bücker
- Institute of Clinical Physiology, Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
| | - Christian Barmeyer
- Institute of Clinical Physiology, Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
| | - Susanne M Krug
- Institute of Clinical Physiology, Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
| | - Michael Fromm
- Institute of Clinical Physiology, Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
| | - Jörg-Dieter Schulzke
- Institute of Clinical Physiology, Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
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13
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Barnes JC, Lumsden RV, Worrell J, Counihan IP, O'Beirne SL, Belperio JA, Fabre A, Donnelly SC, Boylan D, Kane R, Keane MP. CXCR3 Requirement for the Interleukin-13-Mediated Up-Regulation of Interleukin-13Rα2 in Pulmonary Fibroblasts. Am J Respir Cell Mol Biol 2015; 53:217-25. [PMID: 25514189 DOI: 10.1165/rcmb.2013-0433oc] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by fibrosis and abnormal vascularity. IL-13, a profibrotic cytokine that plays a role in IPF, functions through the Jak/STAT pathway after binding to the IL-13 receptor α1 (IL-13Rα1)/IL-4Rα complex. IL-13 also binds to IL-13Rα2, which has been thought to function as a nonsignaling decoy receptor, although possible signaling roles of this receptor have been proposed. CXCR3 and its IFN-inducible ligands-CXCL9, CXCL10, and CXCL11-have been implicated in vascular remodeling and fibroblast motility during the development of IPF. In this study, CXCR3 expression was demonstrated in cultured pulmonary fibroblasts from wild-type BALB/c mice and was found to be necessary for the IL-13-mediated gene and protein up-regulation of IL-13Rα2. In fibroblasts from CXCR3-deficient mice, STAT6 activation was prolonged. This study is the first to demonstrate the expression of CXCR3 in fibroblasts and its association with the expression of IL-13Rα2. Taken together, the results from this study point strongly to a requirement for CXCR3 for IL-13-mediated IL-13Rα2 gene expression. Understanding the function of CXCR3 in IL-13-mediated lung injury may lead to novel approaches to combat the development of pulmonary fibrosis, whether by limiting the effects of IL-13 or by manipulation of angiostatic pathways. The elucidation of the complex relationship between these antifibrotic receptors and manipulation of the CXCR3-mediated regulation of IL-13Rα2 may represent a novel therapeutic modality in cases of acute lung injury or chronic inflammation that may progress to fibrosis.
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Affiliation(s)
- Jennifer C Barnes
- 1 UCD Conway Institute of Biomolecular and Biomedical Research and School of Medicine and Medical Science, University College Dublin, Belfield, Dublin, Ireland
| | - Robert V Lumsden
- 1 UCD Conway Institute of Biomolecular and Biomedical Research and School of Medicine and Medical Science, University College Dublin, Belfield, Dublin, Ireland
| | - Julie Worrell
- 1 UCD Conway Institute of Biomolecular and Biomedical Research and School of Medicine and Medical Science, University College Dublin, Belfield, Dublin, Ireland
| | - Ian P Counihan
- 1 UCD Conway Institute of Biomolecular and Biomedical Research and School of Medicine and Medical Science, University College Dublin, Belfield, Dublin, Ireland
| | - Sarah L O'Beirne
- 1 UCD Conway Institute of Biomolecular and Biomedical Research and School of Medicine and Medical Science, University College Dublin, Belfield, Dublin, Ireland
| | - John A Belperio
- 2 Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; and
| | | | - Seamas C Donnelly
- 1 UCD Conway Institute of Biomolecular and Biomedical Research and School of Medicine and Medical Science, University College Dublin, Belfield, Dublin, Ireland.,4 Respiratory Medicine, St. Vincent's University Hospital, Elm Park, Dublin, Ireland
| | - Denise Boylan
- 1 UCD Conway Institute of Biomolecular and Biomedical Research and School of Medicine and Medical Science, University College Dublin, Belfield, Dublin, Ireland
| | - Rosemary Kane
- 1 UCD Conway Institute of Biomolecular and Biomedical Research and School of Medicine and Medical Science, University College Dublin, Belfield, Dublin, Ireland
| | - Michael P Keane
- 1 UCD Conway Institute of Biomolecular and Biomedical Research and School of Medicine and Medical Science, University College Dublin, Belfield, Dublin, Ireland.,4 Respiratory Medicine, St. Vincent's University Hospital, Elm Park, Dublin, Ireland
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14
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Suzuki A, Leland P, Joshi BH, Puri RK. Targeting of IL-4 and IL-13 receptors for cancer therapy. Cytokine 2015; 75:79-88. [DOI: 10.1016/j.cyto.2015.05.026] [Citation(s) in RCA: 137] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Revised: 05/22/2015] [Accepted: 05/26/2015] [Indexed: 02/03/2023]
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Retraction. Elevated IL-13Ra2 in Intestinal Epithelial Cells From Ulcerative Colitis or Colorectal Cancer Initiates MAPK Pathway. Inflamm Bowel Dis 2015; 21:1736. [PMID: 26067717 PMCID: PMC4547691 DOI: 10.1097/mib.0000000000000529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
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16
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IL-4 and IL-13 signaling in allergic airway disease. Cytokine 2015; 75:68-78. [PMID: 26070934 DOI: 10.1016/j.cyto.2015.05.014] [Citation(s) in RCA: 346] [Impact Index Per Article: 34.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Accepted: 05/15/2015] [Indexed: 12/12/2022]
Abstract
Aberrant production of the prototypical type 2 cytokines, interleukin (IL)-4 and IL-13 has long been associated with the pathogenesis of allergic disorders. Despite tremendous scientific inquiry, the similarities in their structure, and receptor usage have made it difficult to ascertain the distinct role that these two look-alike cytokines play in the onset and perpetuation of allergic inflammation. However, recent discoveries of differences in receptor distribution, utilization/assembly and affinity between IL-4 and IL-13, along with the discovery of unique innate lymphoid 2 cells (ILC2) which preferentially produce IL-13, not IL-4, are beginning to shed light on these mysteries. The purpose of this chapter is to review our current understanding of the distinct roles that IL-4 and IL-13 play in allergic inflammatory states and the utility of their modulation as potential therapeutic strategies for the treatment of allergic disorders.
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Reinisch W, Panés J, Khurana S, Toth G, Hua F, Comer GM, Hinz M, Page K, O'Toole M, Moorehead TM, Zhu H, Sun Y, Cataldi F. Anrukinzumab, an anti-interleukin 13 monoclonal antibody, in active UC: efficacy and safety from a phase IIa randomised multicentre study. Gut 2015; 64:894-900. [PMID: 25567115 DOI: 10.1136/gutjnl-2014-308337] [Citation(s) in RCA: 122] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Accepted: 12/04/2014] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Interleukin 13 (IL-13) is thought to play a key role as an effector cytokine in UC. Anrukinzumab, a humanised antibody that inhibits human IL-13, was evaluated for the treatment of UC. DESIGN In a multicentre, randomised, double-blind, placebo-controlled study, patients with active UC (Mayo score ≥4 and <10) were randomised to anrukinzumab 200, 400 or 600 mg or placebo. Patients received five intravenous administrations over 14 weeks. The primary endpoint was fold change from baseline in faecal calprotectin (FC) at Week 14. Secondary endpoints included safety, pharmacokinetics and IL-13 levels. RESULTS The modified intention-to-treat population included 84 patients (21 patients/arm). Fold change of FC from baseline at Week 14 was not significantly different for any treatment groups compared with the placebo. The study had a high dropout rate, in part, related to lack of efficacy. The exploratory comparisons of each dose were not significantly different from placebo in terms of change from baseline in total Mayo score, clinical response, clinical remission and proportion of subjects with mucosal healing. An increase in serum total IL-13 (free and bound to anrukinzumab) was observed for all anrukinzumab groups but not with placebo. This suggests significant binding of anrukinzumab to IL-13. The safety profile was not different between the anrukinzumab and placebo groups. CONCLUSIONS A statistically significant therapeutic effect of anrukinzumab could not be demonstrated in patients with active UC in spite of binding of anrukinzumab to IL-13. TRIAL REGISTRATION NUMBER ClinicalTrials.gov number NCT01284062.
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Affiliation(s)
- Walter Reinisch
- McMaster University, Hamilton, Ontario, Canada Medical University of Vienna, Vienna, Austria
| | - Julián Panés
- Hospital Clinic I Provincial de Barcelona, CIBERehd, IDIBAPS, Barcelona, Spain
| | | | | | - Fei Hua
- Pfizer Inc, Collegeville, Pennsylvania, USA
| | | | | | - Karen Page
- Pfizer Inc, Collegeville, Pennsylvania, USA
| | | | | | - Hua Zhu
- Pfizer CRDC, Shanghai, China
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18
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Bartolomé RA, García-Palmero I, Torres S, López-Lucendo M, Balyasnikova IV, Casal JI. IL13 Receptor α2 Signaling Requires a Scaffold Protein, FAM120A, to Activate the FAK and PI3K Pathways in Colon Cancer Metastasis. Cancer Res 2015; 75:2434-44. [PMID: 25896327 DOI: 10.1158/0008-5472.can-14-3650] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2014] [Accepted: 04/03/2015] [Indexed: 11/16/2022]
Abstract
IL13 signaling through its receptor IL13Rα2 plays a critical role in colon cancer invasion and liver metastasis, but the mechanistic features of this process are obscure. In this study, we identified a scaffold protein, FAM120A (C9ORF10), as a signaling partner in this process. FAM120A was overexpressed in human colon cancer cell lines and 55% of human colon cancer specimens. IL13Rα2-FAM120A coimmunoprecipitation experiments revealed further signaling network associations that could regulate the activity of IL13Rα2, including FAK, SRC, PI3K, G-protein-coupled receptors, and TRAIL receptors. In addition, FAM120A associated with kinesins and motor proteins involved in cargo movement along microtubules. IL13Rα2-triggered activation of the FAK and PI3K/AKT/mTOR pathways was mediated by FAM120A, which also recruited PI3K and functioned as a scaffold protein to enable phosphorylation and activation of PI3K by Src family kinases. FAM120A silencing abolished IL13-induced cell migration, invasion, and survival. Finally, antibody blockade of IL13Rα2 or FAM120A silencing precluded liver colonization in nude mice or metastasis. In conclusion, we identified FAM120A in the IL13/IL13Rα2 signaling pathway as a key mediator of invasion and liver metastasis in colon cancer.
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Affiliation(s)
- Rubén A Bartolomé
- Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain
| | - Irene García-Palmero
- Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain
| | - Sofía Torres
- Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain
| | - María López-Lucendo
- Proteomics Facility, Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain
| | | | - J Ignacio Casal
- Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain.
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19
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Kasaian MT, Page KM, Fish S, Brennan A, Cook TA, Moreira K, Zhang M, Jesson M, Marquette K, Agostinelli R, Lee J, Williams CMM, Tchistiakova L, Thakker P. Therapeutic activity of an interleukin-4/interleukin-13 dual antagonist on oxazolone-induced colitis in mice. Immunology 2014; 143:416-27. [PMID: 24831554 DOI: 10.1111/imm.12319] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2013] [Revised: 05/08/2014] [Accepted: 05/12/2014] [Indexed: 02/06/2023] Open
Abstract
Interleukin-4 (IL-4) and IL-13 are critical drivers of immune activation and inflammation in ulcerative colitis, asthma and other diseases. Because these cytokines may have redundant function, dual targeting holds promise for achieving greater efficacy. We have recently described a bifunctional therapeutic targeting IL-4 and IL-13 developed on a novel protein scaffold, generated by combining specific binding domains in an optimal configuration using appropriate linker regions. In the current study, the bifunctional IL-4/IL-13 antagonist was evaluated in the murine oxazolone-induced colitis model, which produces disease with features of ulcerative colitis. The bifunctional IL-4/IL-13 antagonist reduced body weight loss throughout the 7-day course of the model, and ameliorated the increased colon weight and decreased colon length that accompany disease. Colon tissue gene expression was modulated in accordance with the treatment effect. Concentrations of serum amyloid P were elevated in proportion to disease severity, making it an effective biomarker. Serum concentrations of the bifunctional IL-4/IL-13 antagonist were inversely proportional to disease severity, colon tissue expression of pro-inflammatory genes, and serum amyloid P concentration. Taken together, these results define a panel of biomarkers signifying engagement of the IL-4/IL-13 pathway, confirm the T helper type 2 nature of disease in this model, and demonstrate the effectiveness of dual cytokine blockade.
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20
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Edin NFJ. The role of interleukin-13 in the removal of hyper-radiosensitivity by priming irradiation. JOURNAL OF RADIATION RESEARCH 2014; 55:1066-1074. [PMID: 24966400 PMCID: PMC4229918 DOI: 10.1093/jrr/rru053] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/22/2014] [Revised: 04/29/2014] [Accepted: 05/23/2014] [Indexed: 06/03/2023]
Abstract
It has previously been demonstrated that the presence of fetal bovine serum is necessary for TGF-β3 (transforming growth factor beta 3)-dependent elimination of low-dose hyper-radiosensitivity (HRS) in cells by 1 h of low-dose-rate γ-irradiation (0.2-0.3 Gy/h). The purpose of the present study was to identify the serum constituent involved. Two human HRS-positive (T-47D, T98G) cell lines were used. The effects of different pretreatments on HRS were investigated using the colony assay. Total inducible nitric oxide synthase (iNOS) levels were measured using a cell-based ELISA assay. The serum factor was identified as interleukin-13 (IL-13). In order for low dose-rate irradiation to eliminate HRS through the TGF-β3-dependent mechanism, the cells must be exposed to IL-13 first. Inhibiting receptor IL-13Rα2 showed that this receptor is involved in the response. Adding IL-13 to serum-free medium restored the properties of full medium but not when an inhibitor of proprotein convertase activity was added together with IL-13. The presence of IL-13 resulted in upregulation of total iNOS protein levels. Thus, this study indicates that IL-13 interacts with the cells though receptor IL-13Rα2 and induces upregulation of iNOS and activation of one or more furin-like proprotein convertases.
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Affiliation(s)
- Nina F Jeppesen Edin
- Department of Physics, Biophysics Group, University of Oslo, PB 1048, Blindern, N-0316 Oslo, Norway
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21
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Li Z, Guan YQ, Liu JM. The role of STAT-6 as a key transcription regulator in HeLa cell death induced by IFN-γ/TNF-α co-immobilized on nanoparticles. Biomaterials 2014; 35:5016-27. [DOI: 10.1016/j.biomaterials.2014.03.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2014] [Accepted: 03/03/2014] [Indexed: 02/08/2023]
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22
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Chandriani S, DePianto DJ, N’Diaye EN, Abbas AR, Jackman J, Bevers J, Ramirez-Carrozzi V, Pappu R, Kauder SE, Toy K, Ha C, Modrusan Z, Wu LC, Collard HR, Wolters PJ, Egen JG, Arron JR. Endogenously Expressed IL-13Rα2 Attenuates IL-13–Mediated Responses but Does Not Activate Signaling in Human Lung Fibroblasts. THE JOURNAL OF IMMUNOLOGY 2014; 193:111-9. [DOI: 10.4049/jimmunol.1301761] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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Ondondo BO. Fallen angels or risen apes? A tale of the intricate complexities of imbalanced immune responses in the pathogenesis and progression of immune-mediated and viral cancers. Front Immunol 2014; 5:90. [PMID: 24639678 PMCID: PMC3944202 DOI: 10.3389/fimmu.2014.00090] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2013] [Accepted: 02/20/2014] [Indexed: 12/13/2022] Open
Abstract
Excessive immune responses directed against foreign pathogens, self-antigens, or commensal microflora can cause cancer establishment and progression if the execution of tight immuno-regulatory mechanisms fails. On the other hand, induction of potent tumor antigen-specific immune responses together with stimulation of the innate immune system is a pre-requisite for effective anti-tumor immunity, and if suppressed by the strong immuno-regulatory mechanisms can lead to cancer progression. Therefore, it is crucial that the inevitable co-existence of these fundamental, yet conflicting roles of immune-regulatory cells is carefully streamlined as imbalances can be detrimental to the host. Infection with chronic persistent viruses is characterized by severe immune dysfunction resulting in T cell exhaustion and sometimes deletion of antigen-specific T cells. More often, this is due to increased immuno-regulatory processes, which are triggered to down-regulate immune responses and limit immunopathology. However, such heightened levels of immune disruption cause a concomitant loss of tumor immune-surveillance and create a permissive microenvironment for cancer establishment and progression, as demonstrated by increased incidences of cancer in immunosuppressed hosts. Paradoxically, while some cancers arise as a consequence of increased immuno-regulatory mechanisms that inhibit protective immune responses and impinge on tumor surveillance, other cancers arise due to impaired immuno-regulatory mechanisms and failure to limit pathogenic inflammatory responses. This intricate complexity, where immuno-regulatory cells can be beneficial in certain immune settings but detrimental in other settings underscores the need for carefully formulated interventions to equilibrate the balance between immuno-stimulatory and immuno-regulatory processes.
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24
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Wang HP, Wang YY, Pan J, Cen R, Cai YK. Evaluation of specific fecal protein biochips for the diagnosis of colorectal cancer. World J Gastroenterol 2014; 20:1332-1339. [PMID: 24574808 PMCID: PMC3921516 DOI: 10.3748/wjg.v20.i5.1332] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2013] [Revised: 09/28/2013] [Accepted: 11/13/2013] [Indexed: 02/07/2023] Open
Abstract
AIM: To develop and initially test a potential fecal protein biochip for the screening of colorectal cancer (CRC).
METHODS: Fecal protein from 20 colorectal cancer patients and 20 healthy controls were extracted from all of the fecal samples and screened for proteomic differences using a Biotin label-based protein array. Candidate proteins were then verified by ELISA. Finally, we will select out the significant protein and a seven-target multiplex fecal protein biochip was generated and tested for 20 fecal samples to determine the effectiveness of the biochip on identifying CRC. And the value of the protein biochip would be discussed.
RESULTS: After tested by protein biochip of the fecal protein from 20 colorectal cancer patients and 20 healthy controls and levels of calprotectin, M2-pyruvatekinase, angiopoietin-2, fibroblast growth factor-23 (FGF-23), proteins of the matrix metalloproteinase, thrombopoietin (TPO) and interleukin-13 (IL-13) were significantly different between CRC and healthy controls. The sensitivity of all the seven proteins combined was 0.7, specificity was 0.4, and area under the receiver operating characteristics was 0.729. The most promising combinations of test proteins were FGF-23, TPO, and IL-13, reaching a sensitivity of 0.7 and a specificity of 0.7. The combination of FGF-23 and TPO scored highest with sensitivity of 0.7 and specificity of 0.8. Its mean that the combination of FGF-23 and TPO has the highest value for the diagnosis of CRC in our study.
CONCLUSION: A protein biochip composed of proteins found to be elevated in the feces of colorectal cancer patients has great potential as a noninvasive diagnostic for colorectal cancer. The addition of new protein biomarkers and technologies, as they are discovered, is an excellent avenue of future research.
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Cruceru ML, Neagu M, Demoulin JB, Constantinescu SN. Therapy targets in glioblastoma and cancer stem cells: lessons from haematopoietic neoplasms. J Cell Mol Med 2013; 17:1218-35. [PMID: 23998913 PMCID: PMC4159024 DOI: 10.1111/jcmm.12122] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2013] [Accepted: 07/27/2013] [Indexed: 12/14/2022] Open
Abstract
Despite intense efforts to identify cancer-initiating cells in malignant brain tumours, markers linked to the function of these cells have only very recently begun to be uncovered. The notion of cancer stem cell gained prominence, several molecules and signalling pathways becoming relevant for diagnosis and treatment. Whether a substantial fraction or only a tiny minority of cells in a tumor can initiate and perpetuate cancer, is still debated. The paradigm of cancer-initiating stem cells has initially been developed with respect to blood cancers where chronic conditions such as myeloproliferative neoplasms are due to mutations acquired in a haematopoietic stem cell (HSC), which maintains the normal hierarchy to neoplastic haematopoiesis. In contrast, acute leukaemia transformation of such blood neoplasms appears to derive not only from HSCs but also from committed progenitors that cannot differentiate. This review will focus on putative novel therapy targets represented by markers described to define cancer stem/initiating cells in malignant gliomas, which have been called ‘leukaemia of the brain’, given their rapid migration and evolution. Parallels are drawn with other cancers, especially haematopoietic, given the similar rampant proliferation and treatment resistance of glioblastoma multiforme and secondary acute leukaemias. Genes associated with the malignant conditions and especially expressed in glioma cancer stem cells are intensively searched. Although many such molecules might only coincidentally be expressed in cancer-initiating cells, some may function in the oncogenic process, and those would be the prime candidates for diagnostic and targeted therapy. For the latter, combination therapies are likely to be envisaged, given the robust and plastic signalling networks supporting malignant proliferation.
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Affiliation(s)
- Maria Linda Cruceru
- Department of Cellular and Molecular Medicine, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
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Zhou R, Qian S, Gu X, Chen Z, Xiang J. Interleukin-13 and its receptors in colorectal cancer (Review). Biomed Rep 2013; 1:687-690. [PMID: 24649010 DOI: 10.3892/br.2013.132] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2013] [Accepted: 07/08/2013] [Indexed: 12/11/2022] Open
Abstract
Interleukin (IL)-13 is an immunoregulatory cytokine secreted by numerous immune cells. Its functions are similar to those of IL-4 and they share a common receptor. This cytokine has been included in recent studies on human tumors and malignant diseases, evoking a scientific interest to investigate the role of IL-13 and its receptors as novel biomarkers and targets for therapy. Colorectal cancer is one of the most common human malignancies, its prognosis is not promising and the efficacy of molecular-targeted therapy has not been established. This review summarizes the currently available data on the role of IL-13 and its receptors in colorectal cancer, including the signaling pathways involved in mediating the effects of IL-13, the role of IL-13 and/or its receptors in the prediction of cancer and several drugs targeting IL-13 or its receptors that are currently under evaluation.
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Affiliation(s)
- Ru Zhou
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Shiguang Qian
- Department of Immunology and General Surgery, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | - Xiaodong Gu
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Zongyou Chen
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Jianbin Xiang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
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Chen W, Sivaprasad U, Gibson AM, Ericksen MB, Cunningham CM, Bass SA, Kinker KG, Finkelman FD, Wills-Karp M, Khurana Hershey GK. IL-13 receptor α2 contributes to development of experimental allergic asthma. J Allergy Clin Immunol 2013; 132:951-8.e1-6. [PMID: 23763980 DOI: 10.1016/j.jaci.2013.04.016] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2012] [Revised: 03/21/2013] [Accepted: 04/05/2013] [Indexed: 01/06/2023]
Abstract
BACKGROUND IL-13 receptor α2 (IL-13Rα2) binds IL-13 with high affinity and modulates IL-13 responses. There are soluble and membrane forms of IL-13Rα2 generated by alternative splicing in mice, but human subjects express only the membrane form of IL-13Rα2 (memIL-13Rα2). OBJECTIVE We determined the role of memIL-13Rα2 in the development of allergic inflammation in mouse models of asthma. METHODS IL-13Rα2-deficient and memIL-13Rα2 lung epithelium-specific transgenic mice were challenged with house dust mite (HDM). Airway hyperresponsiveness (AHR) and inflammation were assessed based on the airway pressure-time index, bronchoalveolar lavage (BAL) cell counts, and lung histology. Mucus production was determined by means of periodic acid-Schiff staining of lung sections, Western blot analysis of chloride channel calcium activated 3 (CLCA3) expression in lung homogenates, and ELISA of Muc5ac in BAL fluid. The expression of cytokines and chemokines was determined by using RT-quantitative PCR. RESULTS In IL-13Rα2-deficient mice AHR and airway inflammation were attenuated compared with levels seen in wild-type mice after HDM challenge. Lung epithelial overexpression of memIL-13Rα2 in the IL-13Rα2-deficient mice reconstituted AHR and inflammation to levels similar to those observed in HDM-challenged wild-type mice. Mucus production was attenuated in lungs from HDM-treated IL-13Rα2-deficient mice, whereas lung epithelial overexpression of memIL-13Rα2 increased mucus production. Lung epithelial overexpression of memIL-13Rα2 had no effect on levels of the soluble form of IL-13Rα2 in serum or BAL fluid and did not affect IL-13-dependent signal transducer and activator of transcription 6 activation in the lungs. CONCLUSION These data collectively support a distinct role for memIL-13Rα2 in the lung and suggest that memIL-13Rα2 might contribute to allergic inflammation.
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Affiliation(s)
- Weiguo Chen
- Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
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29
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Formentini A, Braun P, Fricke H, Link KH, Henne-Bruns D, Kornmann M. Expression of interleukin-4 and interleukin-13 and their receptors in colorectal cancer. Int J Colorectal Dis 2012; 27:1369-1376. [PMID: 22441356 DOI: 10.1007/s00384-012-1456-0] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/07/2012] [Indexed: 02/04/2023]
Abstract
PURPOSE Interleukin-4 (IL-4) and interleukin-13 (IL-13) are anti-inflammatory and immunomodulatory cytokines which can influence cancer-directed immunosurveillance. Nothing is presently known about expression of these cytokines and their receptors (IL-4R and IL-13R) in colorectal cancer. The aim of this study was to characterize their expression in primary colorectal cancer specimens and to evaluate possible functions for this disease. METHODS Expression of IL-4, IL-13, IL-4R, and IL-13R protein was characterized by immunohistochemistry in 359 patients with Union for International Cancer Control stage I-III colorectal cancer and evaluated by uni- and multivariate analysis for their prognostic relevance. RESULTS All four proteins were expressed in colorectal cancer specimens. In the cancer cells, high IL-4, IL-13, IL-4R, and IL-13R immunoreactivity were present in 33 % (118/359), 50 % (181/359), 36 % (129/359), and 42 % (152/359), respectively. Patients with high expression of IL-4, IL-4R, and IL-13R had a lower frequency of lymph node metastases. Expression of IL-13 did not influence the frequency of lymph node metastases. However, high IL-13-immunoreactivity was associated with a better overall survival (p = 0.041). Expression of IL-4, IL-4R, or IL-13R did not influence survival. Multivariate analysis revealed that besides pT classification and tumor recurrence, IL-13 expression was an independent prognostic factor for overall survival. CONCLUSIONS Expression of IL-4, IL-4R, and IL-13R are involved in the process of local metastases in colorectal cancer, while IL-13 expression has an impact on survival. These interleukins and their receptors may become attractive targets for the treatment of colorectal cancer.
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Affiliation(s)
- Andrea Formentini
- Department of General, Visceral, and Transplantation Surgery, University of Ulm, Steinhövelstrasse 9, Ulm, Germany.
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Ingram JL, Kraft M. IL-13 in asthma and allergic disease: asthma phenotypes and targeted therapies. J Allergy Clin Immunol 2012; 130:829-42; quiz 843-4. [PMID: 22951057 DOI: 10.1016/j.jaci.2012.06.034] [Citation(s) in RCA: 199] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2012] [Revised: 06/25/2012] [Accepted: 06/29/2012] [Indexed: 02/07/2023]
Abstract
Decades of research in animal models have provided abundant evidence to show that IL-13 is a key T(H)2 cytokine that directs many of the important features of airway inflammation and remodeling in patients with allergic asthma. Several promising focused therapies for asthma that target the IL-13/IL-4/signal transducer and activator of transcription 6 pathway are in development, including anti-IL-13 mAbs and IL-4 receptor antagonists. The efficacy of these new potential asthma therapies depends on the responsiveness of patients. However, an understanding of how IL-13-directed therapies might benefit asthmatic patients is confounded by the complex heterogeneity of the disease. Recent efforts to classify subphenotypes of asthma have focused on sputum cellular inflammation profiles, as well as cluster analyses of clinical variables and molecular and genetic signatures. Researchers and clinicians can now evaluate biomarkers of T(H)2-driven airway inflammation in asthmatic patients, such as serum IgE levels, sputum eosinophil counts, fraction of exhaled nitric oxide levels, and serum periostin levels, to aid decision making in clinical trials and drug development and to identify subsets of patients who might benefit from therapies. Although it is unlikely that these therapies will benefit all asthmatic patients with this heterogeneous disease, advances in understanding asthma subphenotypes in relation to clinical variables and T(H)2 cytokine responses offer the opportunity to improve the efficacy and safety of proposed therapies for asthma.
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Affiliation(s)
- Jennifer L Ingram
- Division of Pulmonary, Allergy and Critical Care Medicine, Duke University Medical Center, Durham, NC 27710, USA.
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Walczak A, Przybylowska K, Dziki L, Sygut A, Chojnacki C, Chojnacki J, Dziki A, Majsterek I. The lL-8 and IL-13 gene polymorphisms in inflammatory bowel disease and colorectal cancer. DNA Cell Biol 2012; 31:1431-8. [PMID: 22741617 DOI: 10.1089/dna.2012.1692] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Inflammatory bowel diseases (IBD) and colorectal cancer (CRC) are disorders that originate from immune disturbances. In our study, we evaluated the association between the -251 T/A interleukin (IL)-8 and the -1112 C/T IL-13 polymorphisms, the risk of IBD, and CRC development. Genotypes were determined by PCR-restriction fragment length polymorphism in 191 patients with CRC, 150 subjects with IBD, and 205 healthy controls. We found an association between CRC and the presence of the -251 TA genotype and A allele of the IL-8 gene (odds ratios [ORs] 2.28 and 1.65). A similar relationship was observed between these polymorphic variants and ulcerative colitis (OR 2.05 for the -251 TA genotype and OR 1.47 for the -251 A allele) as well as Crohn's disease (ORs 3.11 and 1.56, respectively). Our research also revealed that the CT and TT genotypes of the IL-13 -1112 C/T polymorphism may be connected with a higher risk of CRC (ORs 2.28 and 1.65). The same genotypes affected the susceptibility of IBD (ORs 2.26 and 3.72). Our data showed that the IL-8 -251 T/A and IL-13 -1112 C/T polymorphisms might be associated with the IBD and CRC occurrence and might be used as predictive factors of these diseases in a Polish population.
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Affiliation(s)
- Anna Walczak
- Department of Clinical Chemistry and Biochemistry, Medical University of Lodz, Lodz, Poland
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Barderas R, Bartolomé RA, Fernandez-Aceñero MJ, Torres S, Casal JI. High expression of IL-13 receptor α2 in colorectal cancer is associated with invasion, liver metastasis, and poor prognosis. Cancer Res 2012; 72:2780-2790. [PMID: 22505647 DOI: 10.1158/0008-5472.can-11-4090] [Citation(s) in RCA: 122] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Autocrine secretion of cytokines by metastatic colorectal cancer cells and their role during invasion and liver homing has been poorly characterized. In this study, we used cytokine arrays to analyze the secretomes of poorly and highly metastatic colorectal cancer cells. Compared with poorly metastatic cancer cells, highly metastatic cells expressed increased levels of the immunosuppressive cytokines interleukin (IL)-4 and IL-13 in addition to increased surface expression of the high affinity IL-13 receptor IL-13Rα2, suggesting that IL-13Rα2 mediates IL-13 effects in colorectal cancer cells. Silencing of IL-13Rα2 in highly metastatic cells led to a decrease in adhesion capacity in vitro and a reduction in liver homing and increased survival in vivo, revealing a role for this receptor in cell adhesion, migration, invasion, and metastatic colonization. In support of this, IL-13 signaling activated the oncogenic signaling molecules phosphoinositide 3-kinase, AKT, and SRC in highly metastatic cells. Clinically, high expression of IL-13Rα2 was associated with later stages of disease progression and poor outcome in patients with colorectal cancer. Our findings therefore support a critical role for IL-13Rα2 expression in colon cancer invasion and metastasis.
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Affiliation(s)
- Rodrigo Barderas
- Functional Proteomics, Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain
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Association of -1112 c/t promoter region polymorphism of the interleukin 13 gene with occurrence of colorectal cancer. POLISH JOURNAL OF SURGERY 2012; 83:27-31. [PMID: 22166239 DOI: 10.2478/v10035-011-0004-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Colorectal carcinoma is one of the leading causes of death from cancer amongst adults. Considering its molecular background, cytokines are the key component of the inflammatory microenvironment of these tumors. Investigations that enable better understanding of colorectal cancer concerning the molecular level, may provide important tools for genetic screening of disease high-risk groups, as well as molecular diagnostics for the non-invasive detection of cancer in its early stages.THE AIM OF THE STUDY was to evaluate the association between colorectal cancer and the -1112 C/T single nucleotide polymorphism (SNP) of the interleukin-13 gene. MATERIAL AND METHODS. The study group comprised 150 cancer patients and 170 healthy subject genotypes from the Polish population. Analysis was performed by PCR-restriction fragment length polymorphism (PCR-RFLP). RESULTS. We showed that the CT genotype is connected with a higher risk of colon cancer occurrence (OR 2.51; 95% CI 1.57-4.02; p < 0.0001). We also correlated the polymorphic variants of the IL-13 gene with the clinical characteristics of colorectal cancer patients. We observed no association between the investigated polymorphism and colorectal cancer progression, evaluated by tumor stage, as well as lymph node metastasis. CONCLUSIONS. The presented study suggested the possibility of a connection between the IL-13 gene polymorphism (-1112 C/T) and colorectal cancer risk in the Polish population.
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Yoshioka K, Ueno Y, Tanaka S, Nagai K, Onitake T, Hanaoka R, Watanabe H, Chayama K. Role of natural killer T cells in the mouse colitis-associated colon cancer model. Scand J Immunol 2012; 75:16-26. [PMID: 21815907 DOI: 10.1111/j.1365-3083.2011.02607.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Invariant natural killer T (iNKT) cells are considered innate-like lymphocytes, and regulate the immunity against inflammation and tumorigenesis. However, the impact of iNKT cells in inflammation-associated tumorigenesis remains unclear. In this study, we examined the physiological role of iNKT cells in a mouse colitis-associated colorectal cancer model. C57BL/6 (B6) and Jα18 NKT cell-deficient KO (KO) mice were used. Colitis-associated colorectal cancer was induced by azoxymethane (AOM) and dextran sodium sulfate (DSS). The resulting inflammation and tumours were examined. The surface markers of mononuclear cells from the liver and the colon were assessed by FACS. The levels of IL-13 from the colon were measured by ELISA. α-galactosylceramide (GC), or its close analog OCH, was administered intraperitoneally on the first day of each cycle of DSS-administration. In the AOM/DSS model, hepatic iNKT cells were significantly decreased. In KO mice there were significantly greater numbers of colon tumours and more severe inflammation than in B6 mice. FACS analysis revealed that the population of NK1.1 (+) T cells (non-invariant NKT cells) in the colon was increased when compared to B6 mice. The secretion of IL-13 was increased in the colon of KO mice after AOM/DSS. The number of colon tumours was significantly decreased in the GC-treated group compared to the control group. GC-treatment significantly inhibited IL-13 secretion from the colonic mononuclear cells and the number of colonic NK1.1 (+) T cells was significantly decreased. These results suggest that iNKT cells may play a critical role in the prevention of tumour progression and inflammation in the AOM/DSS model.
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Affiliation(s)
- K Yoshioka
- Department of Medicine and Molecular Science, Hiroshima University, Hiroshima, Japan
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Kawashima R, Kawamura YI, Oshio T, Son A, Yamazaki M, Hagiwara T, Okada T, Inagaki-Ohara K, Wu P, Szak S, Kawamura YJ, Konishi F, Miyake O, Yano H, Saito Y, Burkly LC, Dohi T. Interleukin-13 damages intestinal mucosa via TWEAK and Fn14 in mice-a pathway associated with ulcerative colitis. Gastroenterology 2011; 141:2119-2129.e8. [PMID: 21893119 DOI: 10.1053/j.gastro.2011.08.040] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2010] [Revised: 08/18/2011] [Accepted: 08/23/2011] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS TWEAK, a member of the tumor necrosis factor (TNF) superfamily, promotes intestinal epithelial cell injury and signals through the receptor Fn14 following irradiation-induced tissue damage and during development of colitis in mice. Interleukin (IL)-13, an effector of tissue damage in similar models, has been associated with the pathogenesis of ulcerative colitis (UC). We investigated interactions between TWEAK and IL-13 following mucosal damage in mice. METHODS We compared patterns of gene expression in intestinal tissues from wild-type and TWEAK knockout mice following γ-irradiation. Intestinal explants from these mice were used to detect cell damage induced by IL-13 and TNF-α. Levels of messenger RNA for IL-13, TWEAK, and Fn14 were measured in mucosal samples from patients with UC. RESULTS Based on gene expression analysis, TWEAK mediates γ-irradiation-induced epithelial cell cycle arrest and apoptosis. However, TWEAK alone did not induce damage or apoptosis of primary intestinal epithelial cells. On the other hand, exogenous IL-13 activated caspase-3 in naïve intestinal explants; this process required TWEAK, Fn14, and secretion of endogenous TNF-α which was mediated by ADAM17. Conversely, activation of caspase by exogenous TNF-α required IL-13, TWEAK, and Fn14. In mucosa from patients with UC, messenger RNA levels of IL-13, TWEAK, and Fn14 increased with level of disease severity. CONCLUSIONS IL-13-induced damage of intestinal epithelial cells requires TWEAK, its receptor (Fn14), and TNF-α. IL-13, TNF-α, TWEAK, and Fn14 could perpetuate and aggravate intestinal inflammation in patients with UC.
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Affiliation(s)
- Rei Kawashima
- Department of Gastroenterology, Research Center for Hepatitis and Immunology, Research Institute, Tokyo, Japan
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Kasaian MT, Raible D, Marquette K, Cook TA, Zhou S, Tan XY, Tchistiakova L. IL-13 antibodies influence IL-13 clearance in humans by modulating scavenger activity of IL-13Rα2. THE JOURNAL OF IMMUNOLOGY 2011; 187:561-9. [PMID: 21622864 DOI: 10.4049/jimmunol.1100467] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Human studies using Abs to two different, nonoverlapping epitopes of IL-13 suggested that epitope specificity can have a clinically significant impact on clearance of IL-13. We propose that Ab modulation of IL-13 interaction with IL-13Rα2 underlies this effect. Two Abs were administered to healthy subjects and mild asthmatics in separate dose-ranging studies and allergen-challenge studies. IMA-638 allows IL-13 interaction with IL-13Rα1 or IL-13Rα2 but blocks recruitment of IL-4Rα to the IL-13/IL-13Rα1 complex, whereas IMA-026 competes with IL-13 interaction with IL-13Rα1 and IL-13Rα2. We found ∼10-fold higher circulating titer of captured IL-13 in subjects treated with IMA-026 compared with those administered IMA-638. To understand how this difference could be related to epitope, we asked whether either Ab affects IL-13 internalization through cell surface IL-13Rα2. Humans inducibly express cell surface IL-13Rα2 but lack the soluble form that regulates IL-13 responses in mice. Cells with high IL-13Rα2 expression rapidly and efficiently depleted extracellular IL-13, and this activity persisted in the presence of IMA-638 but not IMA-026. The potency and efficiency of this clearance pathway suggest that cell surface IL-13Rα2 acts as a scavenger for IL-13. These findings could have important implications for the design and characterization of IL-13 antagonists.
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Affiliation(s)
- Marion T Kasaian
- Department of Inflammation and Immunology, Pfizer Research, Cambridge, MA 02140, USA.
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Gut microbiota, probiotics and inflammatory bowel disease. Arch Immunol Ther Exp (Warsz) 2011; 59:161-77. [PMID: 21445715 DOI: 10.1007/s00005-011-0122-5] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2010] [Accepted: 12/13/2010] [Indexed: 02/07/2023]
Abstract
The colonization of humans with commensals is critical for our well-being. This tightly regulated symbiotic relationship depends on the flora and an intact mucosal immune system. A disturbance of either compound can cause intestinal inflammation. This review summarizes extrinsic and intrinsic factors contributing to intestinal dysbiosis and inflammatory bowel disease.
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Abstract
a recent study in a mouse model of colitis has demonstrated that interleukin (Il)‑13, through inhibition of the mixed type 1 and type 17 T‑helper cell inflammatory response, has a protective effect. the decoyreceptor Il‑13rα2 inhibits this protective effect, suggesting blockade of Il‑13rα2 as a potential therapy for patients with IBD.
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Mandal D, Fu P, Levine AD. RETRACTED: REDOX regulation of IL-13 signaling in intestinal epithelial cells: usage of alternate pathways mediates distinct gene expression patterns. Cell Signal 2010; 22:1485-94. [PMID: 20570727 PMCID: PMC3006087 DOI: 10.1016/j.cellsig.2010.05.017] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2009] [Revised: 05/24/2010] [Accepted: 05/30/2010] [Indexed: 01/02/2023]
Abstract
In the classic view interleukin-13 (IL-13) binds to a heterodimer protein complex of the IL-13Ralpha1 and IL-4Ralpha chains and signals through a Janus kinase 1 (JAK1)-signal transducer and activator of transcription 6 (STAT6) mechanism. We recently reported that IL-13 also signals through the IL-13Ralpha2 chain initiating all three mitogen activated protein kinase (MAPK) pathways, and the relative expression of IL-13Ralpha1 and IL-13Ralpha2 modulates one another's transduction pathway. Therefore we investigated whether generation of reactive oxygen species (ROS) as second messengers may serve as a common nexus between these two pathways emanating from the individual IL-13 receptor chains in intestinal epithelial cells (IEC). IL-13 stimulates intracellular ROS synthesis within 5min via IL-13Ralpha1-JAK1-STAT6- and IL-13Ralpha2-MEK1/2-ERK1/2-dependent activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-1 (NOX-1). IL-13-induced ROS generation in turn positively regulates phosphorylation of ERK1/2 and STAT6, yielding a feed forward amplification loop. IL-13 also stimulates the stable, long-term gene expression of two other NADPH oxidases, NOX-4 and DUOX-2, which along with constitutive NOX-1, might facilitate elevated, continuous production of ROS in IL-13-activated IEC. The contribution of each signal transduction pathway initiated by IL-13 engagement to such biological functions as wound healing, inflammation, and apoptosis was mapped for representative, responsive genes. Distinct usage patterns were observed, demonstrating not only that IL-13 signal transduction through STAT6, MAPK, and ROS is regulated in both an antagonistic and cyclic fashion, but also that each pathway plays a specific role in modulating the wound healing and anti-apoptotic capabilities of the intestinal epithelium.
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Affiliation(s)
- Debasmita Mandal
- Department of Pathology, 10900 Euclid Avenue, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4952
| | - Pingfu Fu
- Departments of Epidemiology and Biostatics, 10900 Euclid Avenue, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4952
- Case Comprehensive Cancer Center, 10900 Euclid Avenue, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4952
| | - Alan D. Levine
- Department of Pathology, 10900 Euclid Avenue, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4952
- Departments of Medicine, Pharmacology, 10900 Euclid Avenue, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4952
- Case Comprehensive Cancer Center, 10900 Euclid Avenue, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4952
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