Possible correction of abnormal rheumatoid arthritis synovial cell function by jun D transfection in vitro.

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disorder of joints, and excessive proliferation of and proinflammatory cytokine and collagenase production by synovial cells are a principal cause of joint destruction. Recent studies have revealed that c-jun and jun B promote growth of fibroblasts, whereas jun D suppresses fibroblast proliferation and even antagonizes Ras-mediated transformation of the fibroblasts. We analyzed effects of gene transfer-mediated jun D overexpression of synovial fibroblast-like cells in patients with RA. RA synovial fibroblast-like cells were transiently transfected with jun D expression vector. The transfectants were stimulated with tumor necrosis factor alpha, and their subsequent proliferative responses and proinflammatory cytokine and matrix metalloproteinase (MMP) production at the messenger RNA and protein levels were measured. Transfection with jun D inhibited the proliferation of, and proinflammatory cytokine and MMP production by, RA synovial cells, mainly due to inhibiting their transcription via down-modulation of AP-1 transcription factor. Localized jun D transfection into the synovial cells of affected joints may inhibit aberrant synovial cell function in patients with RA by down-regulating gene transcription. This function suggests a possible clinical application of this gene therapy.