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IL-6 promotes pathogenic Th17 in T1R leprosy reactions by stimulating Il17 producing by IL-6R pathway
Abstract
Background: Leprosy is an infectious disease caused by Mycobacterium Leprae. Reversal reactions (RR) an inflammatory condition present as inflammation of local skin patches. Approximately, 30–40% of leprosy patients have undergone RR during the course of MDT. Previously, we have reported that IL-23 is involved in Th17 cell differentiation and not IL-6 in non-reactions leprosy patients. Subsequently, recent findings by our group on immunopathology of leprosy reactions showed that IL-6 induces Th17 differentiation together with TGF-β in leprosy reactions. As we asked the question that whether IL-6 or IL-23 induced Th17 cells are different in nature?
Methods and materials: A total of 20 newly diagnosed and untreated stable leprosy and reactions patients were recruited. 48 h PBMCs cultures were established with a different combination of recombinants IL-6, IL-23, and TGF-β with or without Mycobacterium Leprae Sonicated Antigen. Subsequently, PBMCs cultures were blocked with either antagonized IL6R or IL23R antibodies. qPCR was used for gene expression analysis of IL-17A, IL17F, IL6R, and IL23R. Different phenotypes of Th17 cells were studied by flowcytometry and culture supernatant was estimated for cytokine ELISA.
Results: In this study, leprosy reactions showed a high percentage of IL17A and IL17F producing CD4+ IL6R+ T cells as compared to stable leprosy patients (p < 0.001). On the other hand, leprosy reactions showed significant low (p < 0.001) IL-17A and F producing CD4+ IL23R+ Th17 cells as compared to stable leprosy patients in 48 h MLSA stimulated cultures. Furthermore, recombinant IL-6, IL23 and TGF-β significantly (p < 0.001) promotes IL17A and IL17F in CD4+ IL6+ T cells. Subsequently, IL6R and IL23R blocking experiments showed significantly (p < 0.01) down-regulated IL-17A and IL17F in T1R reaction as compared to stable leprosy. Conclusion: This study for the first time establishes that pathogenic Th17 cells IL-17 produce via IL-6R pathway in leprosy T1R reactions. Thus, present approaches that specifically target Th17 cells and/or the cytokines that promote their development, such as IL-6, TGF-β and IL-23A may provide more focused treatment strategies for the management of M. Leprae and its reaction. Hence, therapeutic approaches that aim to re-establish homeostasis by decreasing the production of IL-17 by Th17 may prove effective in the control of leprosy reaction.
Methods and materials: A total of 20 newly diagnosed and untreated stable leprosy and reactions patients were recruited. 48 h PBMCs cultures were established with a different combination of recombinants IL-6, IL-23, and TGF-β with or without Mycobacterium Leprae Sonicated Antigen. Subsequently, PBMCs cultures were blocked with either antagonized IL6R or IL23R antibodies. qPCR was used for gene expression analysis of IL-17A, IL17F, IL6R, and IL23R. Different phenotypes of Th17 cells were studied by flowcytometry and culture supernatant was estimated for cytokine ELISA.
Results: In this study, leprosy reactions showed a high percentage of IL17A and IL17F producing CD4+ IL6R+ T cells as compared to stable leprosy patients (p < 0.001). On the other hand, leprosy reactions showed significant low (p < 0.001) IL-17A and F producing CD4+ IL23R+ Th17 cells as compared to stable leprosy patients in 48 h MLSA stimulated cultures. Furthermore, recombinant IL-6, IL23 and TGF-β significantly (p < 0.001) promotes IL17A and IL17F in CD4+ IL6+ T cells. Subsequently, IL6R and IL23R blocking experiments showed significantly (p < 0.01) down-regulated IL-17A and IL17F in T1R reaction as compared to stable leprosy. Conclusion: This study for the first time establishes that pathogenic Th17 cells IL-17 produce via IL-6R pathway in leprosy T1R reactions. Thus, present approaches that specifically target Th17 cells and/or the cytokines that promote their development, such as IL-6, TGF-β and IL-23A may provide more focused treatment strategies for the management of M. Leprae and its reaction. Hence, therapeutic approaches that aim to re-establish homeostasis by decreasing the production of IL-17 by Th17 may prove effective in the control of leprosy reaction.
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Journal Article