INHIBITION OF COLLAGENASE AND STROMELYSIN GENE-EXPRESSION BY INTERFERON-GAMMA IN HUMAN DERMAL FIBROBLASTS IS MEDIATED IN PART VIA INDUCTION OF TRYPTOPHAN DEGRADATION

The expression of the matrix-degrading enzymes collagenase and stromelysin is modulated by a variety of biologic and pharmacologic agents. IFN-gamma has potent effects on metalloproteinase production and therefore may play an important role in preventing excessive connective tissue degradation during inflammation and repair, We investigated the mechanisms of collagenase and stromelysin regulation by IFN-gamma in human dermal fibroblasts. IFN-gamma (300 U/ml) prevented the stimulation of metalloproteinase gene expression by IL-1 beta. In addition, incubation of fibroblasts with IFN-gamma resulted in a marked increase in cellular indoleamine 2,3-dioxygenase (IDO) mRNA, a > 90% depletion of tryptophan, and a corresponding > 30-fold increase in the tryptophan metabolite kynurenine in the culture media, Reducing the concentration of tryptophan from 25 mu M to 0 markedly diminished the ability of fibroblasts to increase collagenase and stromelysin mRNA and collagenase production in response to IL-1 beta. Addition of exogenous tryptophan (25-50 mu g/ml) to cultures that had been tryptophan depleted by pretreatment with IFN-gamma for 48 h restored the fibroblast response to IL-1 beta or PMA, but had no effect on IFN-gamma-induced HLA-DR alpha chain mRNA expression, These results indicate that inhibition of collagenase and stromelysin gene expression by IFN-gamma in fibroblasts is associated with activation of IDO and enhanced cellular tryptophan metabolism, Tryptophan degradation and ensuing tryptophan depletion may account, at least in part, for the inhibitory effect of IFN-gamma on metalloproteinase production in dermal fibroblasts.