INHIBITION OF TYPE-I COLLAGEN PRODUCTION BY DERMAL FIBROBLASTS UPON CONTACT WITH ACTIVATED T-CELLS - DIFFERENT SENSITIVITY TO INHIBITION BETWEEN SYSTEMIC-SCLEROSIS AND CONTROL FIBROBLASTS

Objective. To assess the role of T lymphocyte fibroblast contact in ty pe I collagen production by cultured dermal fibroblasts from normal in dividuals and from patients with diffuse systemic sclerosis (SSc), Met hods. Cell membranes were prepared from activated CD4+ and CD8+ T cell s, or type I T helper (Th1) clones, and added to confluent fibroblast monolayers, Type I collagen production was measured in culture superna tants, and messenger RNA (mRNA) levels of type I procollagen alpha 1 ( pro alpha 1[I]) and matrix metalloproteinase 1 (MMP-1) were evaluated by Northern hybridization analysis, Results. Dose-dependent inhibition of type I collagen production was observed with CD4+ and CD8+ T cells from both SSc patients and controls. Inhibition of type I collagen wa s significantly less pronounced in fibroblasts from SSc patients than in fibroblasts from controls (P < 0.02), Inhibition was not reversed b y the addition of exogenous transforming growth factor beta, interleuk in-4, interleukin-1 receptor antagonist, antitumor necrosis factor, an ti-CD40, or indomethacin, whereas anti-interferon-gamma (IFN gamma) re versed Th1-mediated inhibition. This inhibitory activity aas specific for type I collagen, since mRNA levels of pro alpha 1(I) were decrease d, whereas mRNA levels of MMP-1 were strongly increased. Conclusion. T he production of type I collagen by skin fibroblasts is specifically d own-regulated by membranes from activated T cells. The contact-depende nt regulatory activity exerted by T cells on fibroblasts depends, at l east in part, on the presence of membrane-associated IFN gamma, Howeve r, SSc fibroblasts are more resistant to inhibition than are fibroblas ts from normal individuals.