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

The expression of the matrix-degrading enzymes collagenase and stromel ysin is modulated by a variety of biologic and pharmacologic agents. I FN-gamma has potent effects on metalloproteinase production and theref ore may play an important role in preventing excessive connective tiss ue degradation during inflammation and repair, We investigated the mec hanisms of collagenase and stromelysin regulation by IFN-gamma in huma n dermal fibroblasts. IFN-gamma (300 U/ml) prevented the stimulation o f metalloproteinase gene expression by IL-1 beta. In addition, incubat ion of fibroblasts with IFN-gamma resulted in a marked increase in cel lular indoleamine 2,3-dioxygenase (IDO) mRNA, a > 90% depletion of try ptophan, and a corresponding > 30-fold increase in the tryptophan meta bolite kynurenine in the culture media, Reducing the concentration of tryptophan from 25 mu M to 0 markedly diminished the ability of fibrob lasts to increase collagenase and stromelysin mRNA and collagenase pro duction in response to IL-1 beta. Addition of exogenous tryptophan (25 -50 mu g/ml) to cultures that had been tryptophan depleted by pretreat ment 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 collagenas e and stromelysin gene expression by IFN-gamma in fibroblasts is assoc iated with activation of IDO and enhanced cellular tryptophan metaboli sm, Tryptophan degradation and ensuing tryptophan depletion may accoun t, at least in part, for the inhibitory effect of IFN-gamma on metallo proteinase production in dermal fibroblasts.