Control of extracellular matrix degradation by interferon-gamma. The tryptophan connection.
Interleukin-1 beta (IL-1 beta) is a potent signal for the induction of the matrix-degrading enzymes collagenase and stromelysin. These metalloproteinases (MMP) play a critical role in physiologic and pathologic connective tissue remodeling, and are potential targets for therapeutic manipulation. Treatment of human dermal fibroblasts with interferon-gamma inhibited. Type I collagen gene expression, and abrogated the effect of IL-1 beta on MMP expression. Interferon-gamma also caused a dramatic dose-dependent increase in indoleamine 2,3-dioxygenase mRNA, with consequent depletion of tryptophan and accumulation of kynurenine in the culture media. To examine the role of tryptophan metabolism in the effects of interferon-gamma on matrix-degrading enzymes, exogenous tryptophan was added to tryptophan-depleted media, followed by stimulation of the cultures with IL-1 beta. Supplementation with tryptophan completely overcame the inhibitory effects of interferon-gamma on MMP mRNA expression and metalloproteinase secretion into the media. In contrast mRNA levels for Type I collagen remained profoundly depressed in interferon-gamma-treated cultures in spite of addition of exogenous tryptophan. These results indicate that oxidative tryptophan metabolism mediates the effects of interferon-gamma on MMP gene expression in human fibroblasts.
Division of Rheumatology, Jefferson Medical College, Philadelphia, Pennsylvania 19107, USA.
J
J
Varga
T
T
Yufit
E
E
Hitraya
R R
RR
Brown
D000328:Adult; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis*; D017364:Collagenases / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000187:drug effects; D005347:Fibroblasts; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007700:Kinetics; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis*; D061965:Matrix Metalloproteinase Inhibitors; D012333:RNA, Messenger / Q000096:biosynthesis; D012867:Skin; D014158:Transcription, Genetic / Q000187:drug effects*; D014364:Tryptophan / Q000378:metabolism* / Q000494:pharmacology; D014366:Tryptophan Oxygenase / Q000096:biosynthesis
D007375:Interleukin-1; D061965:Matrix Metalloproteinase Inhibitors; D012333:RNA, Messenger; D007371:Interferon-gamma; D014364:Tryptophan; D003094:Collagen; D014366:Tryptophan Oxygenase; D017364:Collagenases; D019278:Matrix Metalloproteinase 3