IL-6–Mediated Induction of Matrix Metalloproteinase-9 Is Modulated by JAK-Dependent IL-10 Expression in Macrophages

The mechanisms by which IL-6 contributes to the pathogenesis of chronic inflammatory diseases and cancer are not fully understood. We previously reported that cyclooxygenase-2 (Cox-2)–dependent PGE 2 synthesis regulates macrophage matrix metalloproteinase (MMP)-9 expression, an endopeptidase that participates in diverse pathologic processes. In these studies, we determined whether IL-6 regulates the Cox-2→PGE 2 →MMP-9 pathway in murine macrophages. IL-6 coinduced Cox-2 and microsomal PGE synthase-1, and inhibited the expression of 15-hydroxyprostaglandin dehydrogenase, leading to increased levels of PGE 2 . In addition, IL-6 induced MMP-9 expression, suggesting that the observed proteinase expression was regulated by the synthesis of PGE 2 . However, inhibition of PGE 2 synthesis partially suppressed IL-6–mediated induction of MMP-9. In the canonical model of IL-6–induced signaling, JAK activation triggers STAT and MAPK erk1/2 -signaling pathways. Therefore, the ability of structurally diverse JAK inhibitors to block IL-6–induced MMP-9 expression was examined. Inhibition of JAK blocked IL-6–induced phosphorylation of STAT3, but failed to block the phosphorylation of MAPK erk1/2 , and unexpectedly enhanced MMP-9 expression. In contrast, MEK-1 inhibition blocked IL-6–induced phosphorylation of MAPK erk1/2 and MMP-9 expression without affecting the phosphorylation of STAT3. Thus, IL-6–induced MMP-9 expression is dependent on the activation of MAPK erk1/2 and is restrained by a JAK-dependent gene product. Using pharmacologic and genetic approaches, we identified JAK-dependent induction of IL-10 as a potent feedback mechanism controlling IL-6–induced MMP-9 expression. Together, these data reveal that IL-6 induces MMP-9 expression in macrophages via Cox-2–dependent and –independent mechanisms, and identifies a potential mechanism linking IL-6 to the pathogenesis of chronic inflammatory diseases and cancer.