DIFFERENTIAL REGULATION OF MONOCYTE MATRIX METALLOPROTEINASE AND TIMP-1 PRODUCTION BY TNF-ALPHA GRANULOCYTE-MACROPHAGE CSF, AND IL-1-BETA THROUGH PROSTAGLANDIN-DEPENDENT AND PROSTAGLANDIN-INDEPENDENT MECHANISMS

Matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) produced by monocytes are believed to be involved in the migration of these cells through the basement membrane and the ensuing destruction of connective tissue in chronic inflammatory lesions. Because monocyt es encounter a variety of cytokines at these sites,,ve examined the ef fect of cytokines either alone or in combination on the production of monocyte MMPs and TIMP-1. TNF-alpha, granulocyte-macrophage-CSF (GM-CS F), or IL-1 beta when added individually enhanced the endogenous level s of 92-kDa gelatinase (MMP-9) and TIMP-1 but failed to induce interst itial collagenase (MMP-1). However, GM-CSF, when added with either TNF -alpha or IL-1 beta, induced MMP-1 and synergistically enhanced MMP-9 and TIMP-1, Th2 cytokines, such as IL-4, inhibited the induction of MM Ps and TIMP-1 by TNF-alpha, GM-CSF, and IL-1, Cytokine stimulation of MMP-1 was due, at least in part, to an increase in the release of arac hidonic acid and PG E-2 (PGE(2)), because inhibition of MMP-1 by indom ethacin could be reversed by exogenous PGE(2). In contrast to MMP-1, c ytokine stimulation of MMP-9 and TIMP-1 was unaffected by indomethacin . The PGE(2)-independent induction of monocyte MMP-9 and TIMP-1 by the se cytokines differed from stimulation of MMP-9 and TIMP-1 by LPS, whi ch is in large part PG-dependent. In addition, LPS stimulated higher l evels of MMP-1 whereas cytokines induced higher levels of MMP-9 and TI MP-1, This is the first demonstration that monocyte MMP-1 can be induc ed by cytokines and that MMP-1, MMP-9, and TIMP-1 are differentially r egulated by cytokines through PG-dependent and -independent mechanisms .