A major characteristic of scleroderma (SSc) fibroblasts is an increased biosynthesis of extracellular matrix macromolecules that could be linked to impaired regulation by cytokines. We investigated the effects of two cytokines from T lymphocytes, interleukin-4 (IL-4) and interferon-γ (IFN-γ), on normal and scleroderma fibroblast cultures. In both types of fibroblasts, IL-4 strongly stimulated collagen synthesis, whereas IFN-γ was a potent inhibitor. The effects of these cytokines were localized at the pre-translational level, and both mRNA steady-state level and protein synthesis were equally affected. SSc fibroblasts responded to IL-4 and IFN-γ as well as normal fibroblasts. When fibroblasts were incubated with combinations of both cytokines, IFN-γ completely suppressed the stimulation of collagen gene expression induced by IL-4. Northern blot and western blot analyses demonstrated that IFN-γ induced a rapid and strong decrease in the expression of the IL-4 receptor-α by fibroblasts. This effect might explain the antagonistic effects of IFN-γ on the IL-4–dependent enhancement of collagen synthesis. Thus, our data suggest that the alteration of collagen production in scleroderma fibroblasts does not depend on an altered sensitivity of these cells to stimulatory or inhibitory cytokines but is more likely the consequence of an imbalance in the local production of autocrine or paracrine regulatory factors.