Interleukin-18 induces EMMPRIN expression in primary cardiomyocytes via JNK/Sp1 signaling and MMP-9 in part via EMMPRIN and through AP-1 and NF-κB activation

Venkatapuram Seenu Reddy, Sumanth D. Prabhu, Srinivas Mummidi, Anthony J. Valente, Balachandar Venkatesan, Prakashsrinivasan Shanmugam, Patrice Delafontaine, Bysani Chandrasekar

Research output: Contribution to journalArticle

56 Scopus citations

Abstract

IL-18 and the extracellular matrix metalloproteinase (MMP) inducer (EMMPRIN) stimulate the expression of proinflammatory cytokines and MMPs and are elevated in myocardial hypertrophy, remodeling, and failure. Here, we report several novel findings in primary cardiomyocytes treated with IL-18. First, IL-18 activated multiple transcription factors, including NF-κB (p50 and p65), activator protein (AP)-1 (cFos, cJun, and JunD), GATA, CCAAT/enhancer-binding protein, myocyte-specific enhancer-binding factor, interferon regulatory factor-1, p53, and specific protein (Sp)-1. Second, IL-18 induced EMMPRIN expression via myeloid differentiation primary response gene 88/IL-1 receptor-associated kinase/TNF receptor-associated factor-6/JNK- dependent Sp1 activation. Third, IL-18 induced a number of MMP genes, particularly MMP-9, at a rapid rate as well as tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-3 at a slower rate. Finally, the IL-18 induction of MMP-9 was mediated in part via EMMPRIN and through JNK- and ERK-dependent AP-1 activation and p38 MAPK-dependent NF-κB activation. These results suggest that the elevated expression of IL-18 during myocardial injury and inflammation may favor EMMPRIN and MMP induction and extracellular matrix degradation. Therefore, targeting IL-18 or its signaling pathways may be of potential therapeutic benefit in adverse remodeling.

Original languageEnglish (US)
Pages (from-to)H1242-H1254
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume299
Issue number4
DOIs
StatePublished - Oct 2010

Keywords

  • Activator protein-1
  • C-Jun NH terminal kinase
  • Extracellular matrix
  • Extracellular matrix metalloproteinase inducer
  • Matrix metalloproteinase
  • Myocardial remodeling
  • Nuclear factor-κB
  • Specific protein-1
  • Tissue inhibitor of metalloproteinase

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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