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, Granulocyte-Macrophage CSF, and IL-1ß Through Prostaglandin-Dependent and -Independent Mechanisms
Immunopathology Section, National Institute of Dental Research, National Institutes of Health, Bethesda, MD 20892
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 monocytes encounter a variety of cytokines at these sites, we
examined the effect of cytokines either alone or in combination on the
production of monocyte MMPs and TIMP-1. TNF-
,
granulocyte-macrophage-CSF (GM-CSF), or IL-1ß when added individually
enhanced the endogenous levels of 92-kDa gelatinase (MMP-9) and TIMP-1
but failed to induce interstitial collagenase (MMP-1). However, GM-CSF,
when added with either TNF- or IL-1ß, induced MMP-1 and
synergistically enhanced MMP-9 and TIMP-1. Th2 cytokines, such as IL-4,
inhibited the induction of MMPs and TIMP-1 by TNF-, GM-CSF, and
IL-1. Cytokine stimulation of MMP-1 was due, at least in part, to an
increase in the release of arachidonic acid and PG E2
(PGE2), because inhibition of MMP-1 by indomethacin could
be reversed by exogenous PGE2. In contrast to MMP-1,
cytokine stimulation of MMP-9 and TIMP-1 was unaffected by
indomethacin. The PGE2-independent induction of monocyte
MMP-9 and TIMP-1 by these cytokines differed from stimulation of MMP-9
and TIMP-1 by LPS, which is in large part PG-dependent. In addition,
LPS stimulated higher levels of MMP-1 whereas cytokines induced higher
levels of MMP-9 and TIMP-1. This is the first demonstration that
monocyte MMP-1 can be induced by cytokines and that MMP-1, MMP-9, and
TIMP-1 are differentially regulated by cytokines through PG-dependent
and -independent mechanisms.
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U. T. Shankavaram, W.-C. Lai, S. Netzel-Arnett, P. R. Mangan, J. A. Ardans, N. Caterina, W. G. Stetler-Stevenson, H. Birkedal-Hansen, and L. M. Wahl Monocyte Membrane Type 1-Matrix Metalloproteinase. PROSTAGLANDIN-DEPENDENT REGULATION AND ROLE IN METALLOPROTEINASE-2 ACTIVATION J. Biol. Chem., May 25, 2001; 276(22): 19027 - 19032. [Abstract] [Full Text] [PDF]
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