UNCOORDINATE REGULATION OF COLLAGENASE, STROMELYSIN, AND TISSUE INHIBITOR OF METALLOPROTEINASES GENES BY PROSTAGLANDIN-E(2) - SELECTIVE ENHANCEMENT OF COLLAGENASE GENE-EXPRESSION IN HUMAN DERMAL FIBROBLASTS INCULTURE

The degradative effects of interleukin-1 (IL-1) on the extracellular m atrix of connective tissue are mediated primarily by metalloproteinase s and prostaglandins. Clinical observations suggest that these effects can be prevented, to some extent, by the use of non-steroidal anti-in flammatory drugs. We have examined the role of prostaglandin E2 (PGE2) in IL-1 -induced gene expression by human skin fibroblasts in culture . Incubation of confluent fibroblast cultures with varying concentrati ons (0.01-1.0 mug/ml) of PGE2 led to a dose-dependent elevation of col lagenase mRNA steady-state levels, the promoter activity, and the secr etion of the protein, whereas relatively little effect was observed on stromelysin and TIMP gene expression. Exogenous PGE2 had no additive or synergistic effect with IL-1 on collagenase gene expression. Furthe rmore, commonly used non-steroidal anti-inflammatory drugs (indomethac in, acetyl salicylic acid and ibuprofen), at doses which block prostag landin synthesis in cultured fibroblasts, failed to counteract IL-1-in duced collagenase and stromelysin gene expression, nor did they affect TIMP expression. Although the effects of PGE2 did not potentiate thos e of IL-1 on collagenase gene expression in vitro, one could speculate that massive production of PGE2 by connective tissue cells in vivo in response to inflammatory mediators such as IL-1 or tumor necrosis fac tor-alpha, could lead to sustained expression of collagenase in connec tive tissue cells after clearance of the growth factors. (C) 1994 Wile y-Liss, Inc.