ANTAGONISTIC EFFECTS OF INTERFERON-GAMMA AND INTERLEUKIN-4 ON FIBROBLAST-CULTURES

A major characteristic of scleroderma (SSc) fibroblasts is an increase d biosynthesis of extracellular matrix macromolecules that could be li nked to impaired regulation by cytokines. We investigated the effects of two cytokines from T lymphocytes, interleukin-4 (IL-4) and interfer on-gamma (IFN-gamma), on normal and scleroderma fibroblast cultures. I n both types of fibroblasts, IL-4 strongly stimulated collagen synthes is, whereas IFN-gamma was a potent inhibitor, The effects of these cyt okines were localized at the pre-translational level, and both mRNA st eady-state level and protein synthesis were equally affected, SSc fibr oblasts responded to IL-4 and IFN-gamma as well as normal fibroblasts, When fibroblasts were incubated with combinations of both cytokines, IFN-gamma completely suppressed the stimulation of collagen gene expre ssion induced by IL-4. Northern blot and western blot analyses demonst rated that IFN-gamma induced a rapid and strong decrease in the expres sion of the IL-4 receptor-alpha by fibroblasts. This effect might expl ain the antagonistic effects of IFN-gamma on the IL-4-dependent enhanc ement of collagen synthesis. Thus, our data suggest that the alteratio n of collagen production in scleroderma fibroblasts does not depend on an altered sensitivity of these cells to stimulatory or inhibitory cy tokines but is more likely the consequence of an imbalance in the loca l production of autocrine or paracrine regulatory factors.