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

Abstract

Background: Involvement of IL-6 in the pathogenesis of rheumatoid arthritis has recently been demonstrated, but the mechanism of its production by rheumatoid synoviocytes is still poorly defined. Objective: The purpose of this study was to clarify the cellular and molecular 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 method. 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 mobility 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-α and IL-1. Deletion analysis showed that the IL-6 promoter was regulated by 2 positive elements (–159 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 production. The binding activity of NF-κB p50/p65 heterodimer and RBP-Jκ was enhanced in these clones. Conclusion: IL-6 production by rheumatoid synoviocytes is autonomously upregulated at the transcriptional level and spontaneous activation of NF-κB and RBP-Jκ seems to be involved. (J Allergy Clin Immunol 1999;103:S437-44.)