Inhibition of collagenase-3 (MMP-13) expression in transformed human keratinocytes by interferon-gamma is associated with activation of extracellularsignal-regulated kinase-1,2 and STAT1

Collagenase-3 (MMP-13) is characterized by an exceptionally wide substrate specificity and restricted expression, MMP-13 is specifically expressed by transformed human keratinocytes in squamous cell carcinomas in who and its expression correlates with their invasion capacity. Here, we show, that int erferon-gamma (IFN-gamma) markedly inhibits expression of MMP-13 by human c utaneous SCC cells (UT-SCC-7) and by ras-transformed human epidermal kerati nocytes (A-5 cells) at the transcriptional level. In addition, IFN-gamma in hibits collagenase-1 (MMP-1) expression in these cells, IFN-gamma, abolishe d the enhancement of MMP-13 and MMP-1 expression by transforming growth fac tor-beta (TGF-beta) and tumor necrosis factor-alpha (TNF-alpha), and inhibi ted invasion of A-5 cells through type I collagen. IFN-gamma also rapidly a nd transiently activates extracellular signal-regulated kinase 1,2 (ERK1,2) and blocking ERK1,2 pathway (Raf/MEK1,2/ERK1,2) by specific MEK1,2 inhibit or PD98059 partially (by 50%) prevents Ser-727 phosphorylation of STAT1 and suppression of MMP-13 expression by IFN-gamma, Furthermore, Ser-727 phosph orylation of STAT1 by ERK1,2, or independently of ERK1,2 activation is asso ciated with marked reduction in MMP-13 expression. These observations ident ify a novel role for IFN-gamma as a potent inhibitor of collagenolytic acti vity and invasion of transformed squamous epithelial cells, and show that i nhibition of MMP-13 expression by IFN-gamma involves activation of ERK1,2 a nd STAT1.