TNF-ALPHA AND IL-1-BETA SELECTIVELY INDUCE EXPRESSION OF 92-KDA GELATINASE BY HUMAN MACROPHAGES

Macrophages are present in inflammatory tissue sites where abnormal de gradation of the extracellular matrix takes place. To evaluate the pot ential of macrophages to participate in such matrix destruction, we st udied the effects of th ree cytokines present in inflammatory tissue s ites, TNF-alpha, IL-1 beta, and IFN-gamma, on the production of three matrix-degrading metalloproteinases, interstitial collagenase, stromel ysin, and 92-kDa gelatinase, as well as their natural inhibitor, TIMP- 1 (tissue inhibitor of metalloproteinases number 1), by human monocyte -derived macrophages differentiated in vitro. Spontaneous production o f interstitial collagenase and stromelysin by these cells was minimal, and was not influenced by the cytokines. In contrast, the cells secre ted substantial basal amounts of 92-kDa gelatinase, the secretion of w hich was stimulated (2- to 15-fold; on average 5-fold) by both TNF-alp ha and IL-1 beta, while the production of TIMP-1 was unaffected. IFN-g amma suppressed the production of the 92-kDa gelatinase induced by TNF -alpha and IL-1 beta. TNF-alpha and IL-1 beta regulated the expression of 92-kDa gelatinase by monocyte-derived macrophages at the pretransl ational level. The results show that expression of 92-kDa gelatinase, but not its natural inhibitor TIMP-1, by human tissue-type macrophages is selectively up-regulated by proinflammatory cytokines; which sugge sts that these cells, when actually present in an inflammatory environ ment, will actively participate in the destruction of the extracellula r matrix.