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-induced matrix metalloproteinase-9 expression in monocytes
* Department of Immunology, Weizmann Institute of Science, Rehovot, and
Immunology Research Unit, Carmel Medical Center, Haifa, Israel
Correspondence: Ofer Lider, Ph.D., Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel. E-mail: ofer.lider{at}weizmann.ac.il
The inflammatory response is marked by the release of several cytokines
with multiple roles in regulating leukocyte activities, including
the secretion of matrix metalloproteinases (MMPs). Although
the effects of individual cytokines on monocyte MMP expression have
been studied extensively, few studies have examined the influence of
combinations of cytokines, which are likely present at inflammatory
sites. Herein, we report our investigation of the combinatorial effects
of tumor necrosis factor (TNF)-
and transforming growth factor
(TGF)-ß on MMP-9 synthesis. We found that TGF-ß suppressed
TNF--induced MMP-9 secretion by MonoMac-6 monocytic cells in a
dose-dependent manner, with a maximal effect of TGF-ß observed at 1
ng/ml. Such suppression was likely regulated at the pretranslational
level, because steady-state mRNA levels of TNF--induced MMP-9
were reduced by TGF-ß, and pulse-chase radiolabeling also showed a
decrease in new MMP-9 protein synthesis. The suppressive effects of
TGF-ß were time dependent, because short exposures to TNF- before
TGF-ß or simultaneous exposure to both cytokines efficiently reduced
MMP-9 secretion. Expression of the tissue inhibitor of
metalloproteinases (TIMP)-1 and TNF- receptors was unaffected by
either cytokine individually or in combination. Affinity binding with
radiolabeled TGF-ß demonstrated that levels of TGF-ß receptors were
not increased after preincubation with TGF-ß. Suppression of
TNF-induced MMP-9 secretion by TGF-ß correlated with a reduction
in prostaglandin E2 (PGE2) secretion.
Furthermore, the effect of TGF-ß or indomethacin on blockage of
TNF--stimulated MMP-9 production was reversed by the addition of
either exogenous PGE2 or the cyclic AMP (cAMP) analogue
Bt2cAMP. Thus, we concluded that TGF-ß acts as a potent
suppressor of TNF--induced monocyte MMP-9 synthesis via a
PGE2- and cAMP-dependent mechanism. These results suggest
that various combinations of cytokines that are present at inflammatory
sites, as well as their balance during different stages of
inflammation, may provide the signals necessary for directing
MMP-mediated leukocyte activities.
Key Words: enzymes • growth factors • inflammation • extracellular matrix
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