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Transforming growth factor‐β suppresses tumor necrosis factor α‐induced matrix metalloproteinase‐9 expression in monocytes

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)‐α and transforming growth factor (TGF)‐β on MMP‐9 synthesis. We found that TGF‐β suppressed TNF‐α‐induced MMP‐9 secretion by MonoMac‐6 monocytic cells in a dose‐dependent manner, with a maximal effect of TGF‐β observed at 1 ng/ml. Such suppression was likely regulated at the pretranslational level, because steady‐state mRNA levels of TNF‐α‐induced MMP‐9 were reduced by TGF‐β, and pulse‐chase radiolabeling also showed a decrease in new MMP‐9 protein synthesis. The suppressive effects of TGF‐β were time dependent, because short exposures to TNF‐α before TGF‐β or simultaneous exposure to both cytokines efficiently reduced MMP‐9 secretion. Expression of the tissue inhibitor of metalloproteinases (TIMP)‐1 and TNF‐α receptors was unaffected by either cytokine individually or in combination. Affinity binding with radiolabeled TGF‐β demonstrated that levels of TGF‐β receptors were not increased after preincubation with TGF‐β. Suppression of TNFα‐induced MMP‐9 secretion by TGF‐β correlated with a reduction in prostaglandin E2 (PGE2) secretion. Furthermore, the effect of TGF‐β or indomethacin on blockage of TNF‐α‐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‐β acts as a potent suppressor of TNF‐α‐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.