Interleukin-22 promotes Th17 cells differentiation through up-regulating IL-6 production by rheuma-toid arthritis synovial fibroblasts
Objective To investigate the effects of interleukine-22 （ IL-22 ） on the expression of interleukin-6 （IL-6） by rheumatoid arthritis synovial fibroblasts （RASF）, and to analyze their association with IL-17＋CD4＋T （Th17） cells differentiation.Methods RASF were isolated from six patients with rheu-matoid arthritis （ RA） and cultured in vitro.The expression of IL-6 at mRNA and protein levels by RASF were detected by qRT-PCR analysis and ELISA after treatment with different concentrations of IL -22 for dif-ferent periods of time.Anti-IL-22R1 blocking antibody and inhibitor assay were used to analyze the specific receptor and its downstream signaling pathways associated with IL-6 production.IL-22 pre-treated RASF and CD4＋T cells were co-cultured for 3 days in the presence or absence of anti-IL-22R1 or anti-IL-6 to measure the percentage of Th 17 cells by flow cytometry .Results The expression of IL-6 by RASF was increased up-on IL-22 stimulation in a dose and time dependent manner （P〈0.05）, and that was closely related to IL-22R1 and its downstream signaling pathways of p38 and JAK2 （P〈0.05）.Coculturing CD4＋T cells with RASF and Transwell system indicated that the percentage of Th 17 cells was increased in IL-22 pre-treated group as compared with that in IL-22 untreated group , but it could be downregulated by either blocking IL-22R1 or IL-6.Conclusion IL-22 promoted the expression of IL-6 by RASF and further enhanced Th 17 differentiation.Neutralizing IL-22 in synovium of patients with RA might be an effective therapeutic strategy for RA treatment. 
 
Key words: 
Interleukine-22; Th17 cell differentiation; Interleukine-6; Synovial fibroblasts; Rheumatoid arthritis