To assess the role of T lymphocyte-fibroblast contact in type I collagen production by cultured dermal fibroblasts from normal individuals and from patients with diffuse systemic sclerosis (SSc).Methods.
Cell membranes were prepared from activated CD4+ and CD8+ T cells, or type 1 T helper (Th1) clones, and added to confluent fibroblast monolayers. Type I collagen production was measured in culture supernatants, and messenger RNA (mRNA) levels of type I procollagen α1 (proα1[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 was significantly less pronounced in fibroblasts from SSc patients than in fibroblasts from controls (P < 0.02). Inhibition was not reversed by the addition of exogenous transforming growth factor β, interleukin-4, interleukin-1 receptor antagonist, anti-tumor necrosis factor, anti-CD40, or indomethacin, whereas anti-interferon-γ (IFNγ) reversed Th1-mediated inhibition. This inhibitory activity was specific for type I collagen, since mRNA levels of proα1(I) were decreased, whereas mRNA levels of MMP-1 were strongly increased.Conclusion.
The production of type I collagen by skin fibroblasts is specifically down-regulated by membranes from activated T cells. The contact-dependent regulatory activity exerted by T cells on fibroblasts depends, at least in part, on the presence of membrane-associated IFNγ. However, SSc fibroblasts are more resistant to inhibition than are fibroblasts from normal individuals.