Interferon-gamma reverses the stimulation of collagen but not fibronectin gene expression by transforming growth factor-beta in normal human fibroblasts.

It has recently become apparent that several cytokines and growth factors are capable of modulating fibroblast proliferation and biosynthetic activity. To understand the role of these factors in connective tissue regulation, we examined the effects of the simultaneous addition of interferon-gamma (IFN-gamma) and transforming growth factor-beta (TGF-beta) on normal human dermal fibroblast collagen and fibronectin production. In addition, in vitro transcription rates and steady-state mRNA levels for these molecules were determined by nuclear run-off assays and Northern and dot-blot hybridization using specific human cDNA probes. Treatment of cultures with TGF-beta caused stimulation of collagen and fibronectin production. Addition of IFN-gamma to the TGF-beta-treated cultures abrogated the stimulatory effects of TGF-beta on collagen production in a dose-dependent manner and resulted in a net inhibition of collagen production. In contrast, the increase in fibronectin synthesis induced by TGF-beta was augmented further by IFN-gamma. These changes in collagen and fibronectin production were accompanied by parallel changes in the steady-state mRNA levels for these proteins. The effects of TGF-beta plus IFN-gamma on fibronectin gene expression appeared to be mediated entirely by transcriptional mechanisms, whereas the effects on collagen gene expression resulted from a combination of transcriptional and post-transcriptional events.