IL-6-mediated induction of matrix metalloproteinase-9 is modulated by JAK-dependent IL-10 expression in macrophages

Poonam Kothari, Roberto Pestana, Rim Mesraoua, Rim Elchaki, K. M. Faisal Khan, Andrew J. Dannenberg, Domenick J. Falcone

Research output: Contribution to journalArticle

71 Scopus citations

Abstract

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 PGE2 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→PGE2→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 PGE2. In addition, IL-6 induced MMP-9 expression, suggesting that the observed proteinase expression was regulated by the synthesis of PGE2. However, inhibition of PGE2 synthesis partially suppressed IL-6.mediated induction of MMP-9. In the canonical model of IL-6.induced signaling, JAK activation triggers STAT and MAPKerk1/2-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 MAPKerk1/2, and unexpectedly enhanced MMP-9 expression. In contrast, MEK-1 inhibition blocked IL-6.induced phosphorylation of MAPKerk1/2 and MMP-9 expression without affecting the phosphorylation of STAT3. Thus, IL-6.induced MMP-9 expression is dependent on the activation of MAPKerk1/2 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.

Original languageEnglish (US)
Pages (from-to)349-357
Number of pages9
JournalJournal of Immunology
Volume192
Issue number1
DOIs
StatePublished - Jan 1 2014

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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