IL-6 synthesis by rheumatoid synoviocytes is autonomously upregulated at the transcriptional level

Background: Involvement of IL-6 in the pathogenesis of rheumatoid arthritis has recently been demonstrated, but the mechanism of its production by rhe umatoid synoviocytes is still poorly defined. Objective: The purpose of this study was to clarify the cellular and molecu lar mechanisms involved in the spontaneous production of IL-6 by fibroblast -like synoviocytes obtained from patients with rheumatoid arthritis. Methods: Cloned synoviocytes were established by the limiting dilution meth od. IL-6 synthesis was evaluated by ELISA and Northern blot analysis. IL-6 gene transcription and transcription factors were analyzed by the transient transfection of luciferase reporter plasmids and the electrophoretic mobil ity shift assay, respectively. Results: IL-6 synthesis by cloned rheumatoid synoviocytes was spontaneously upregulated at the transcriptional level. Enhanced IL-6 production by high -producing clones was independent of cytokines from other cell populations or autocrine production of tumor necrosis factor-a and IL-I, Deletion analy sis showed that the IL-6 promoter was regulated by 2 positive elements (-15 9 to -142 base pair and -77 to -59 base pair). The transcriptional activity of the latter element was upregulated in clones showing high IL-6 producti on. The binding activity of NF-KB p50/p65 heterodimer and RBP-Ja was enhanc ed in these clones. Conclusion: IL-6 production by rheumatoid synoviocytes is autonomously upre gulated at the transcriptional level and spontaneous activation of NF-kappa B and RBP-J kappa seems to be involved.