Mechanisms Of The Production Of Cytokine Interleukin-6 In Human FLS Induced By Interleukin-27

Objective: Rheumatoid arthritis(RA)is an inflammatory autoimmune disease characterized by the destruction of joint cartilage and inflammation of the synovium.Fibroblast-like synoviocytes(FLS)are resident mesenchymal cells of synovial joints and have been recognized to play an important role in the immunopathogenesis of RA.Activation of FLS in the onset of RA leads to the production of a broad array of cell surface and soluble mediators that lead to the promotion of inflammation and tissue destruction.However,the detailed immunopathological responses and mechanisms of the activation of FLS in RA have not been well elucidated.In the present study,we have investigated the mechanisms of the activation of human FLS induced by interleukin(IL)-27 and the underlying intracellular signaling molecules were determined.Methods: After treatment of human FLS with IL-27 for 48 hous,concentration of IL-6 in culture supernatant was measured by ELISA.Human FLS were treated with signal pathway inhibitor for 1 hour,and then treated with IL-27 for 48 hours,and the supernatant of IL-6 was detected by ELISA.IL-27 treatment of FLS at different time points,the intracellular signaling pathway phosphorylation level was detected by western blot.Results: IL-27 could significantly induce the release of IL-6 from both control and RA-FLS,and it was in a dose and time dependant manner.IL-27 could induce significant phosphorylation of JAK-2 and JNK in both RA and control FLS.JAK inhibitor AG490 and JNK inhibitor SP600125 could suppress IL-27 induced IL-6 release from both control and RA-FLS.Conclusion: IL-27 up-regulates the release of IL-6 from FLS by activating JAK2 and JNK signaling pathways.Our results therefore provide a new insight into the IL-27-activated immunopathological mechanisms mediated by distinct intracellular signal transductions in joint inflammation of RA.