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논문분류	춘계학술대회 초록집
제목	Stat3 and nf-kb activation through the il-6 amplifier loop in chronic antibody-mediated rejection from renal allograft transplantation.
저자	Mantabya Singh
출판정보	2023; 2023(1):
키워드
초록	Objectives: IL-6 is a most important cytokine that plays a central role in the development of chronic inflammation. Recently, non-immune cells like fibroblast have been postulated to mediate chronic allograft rejection via activation of IL-6 amplifier loop (IL-6+IL-17) via NFκB and STAT3 signalling pathway. Our objective of the study is toevaluate IL-6 amplifier loop activation by IL-6 and Il-17 and pro-Inflammatory pathway analysis (NFκB and STAT3) in chronic antibody-mediated rejection (CABMR) in renal transplant recipients. Methods: Cultured fibroblasts from CABMR patients (n=6) were stimulated with IL-6 (20ng/l), IL-17 (50ng/l), and IL-6 plus IL-17 for 24 hours. As markers of IL-6 amplifier loop activation, ELISA measured IL-6, MCP-1, and CCL20 levels in culture supernatants. In stimulated fibroblasts, the IL-6, MCP1, CCL20, and SOCS3 genes expression was measured by Real-Time PCR. The fibroblasts from CABMR patients were lysed with Lysis buffer, subjected to SDS-PAGE and western blotting with anti-STAT3, anti-phospho-STAT3, anti-NFFB p65 and anti-phospho-NFFB p65 antibodies. Results: IL-6 and IL-17 synergistically increased IL-6, CCL-20 & MCP-1 production in culture supernatant from fibroblasts.Synergistic activation of IL-6 and IL-17 significantly increased IL-6, MCP1, and CCL20 gene expression, whereas SOCS3 was downregulated. Activation of the IL-6 amplifier loop caused activation of the NFkB and STAT3 signalling pathways in non-immune cells such as fibroblasts derived from CABMR patients. There was a significant reduction in IL-6, CCL-20 & MCP-1 concentration in culture supernatant withIL-6 and IL-17 inhibitors together and mRNA expression of IL-6, CCL-20 & MCP-1 was significantly reduced while SOCS3 gene expression was upregulated Conclusions: In humans after kidney transplantation, IL-6 amplifier activation plays an active role in chronic rejection responses. Inhibition of IL-6 with Anti-IL-6 (Tocilizumab) and inhibition of IL-17 with Anti-IL-17 reduce tissue injury markers (IL-6, MCP1, CCL20) and rejection of allografts. so, the IL-6 amplifier may be a therapeutic target for Chronic transplant rejection.
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