EMMPRIN activates multiple transcription factors in cardiomyocytes, and induces interleukin-18 expression via Rac1-dependent PI3K/Akt/IKK/NF-kappaB andMKK7/JNK/AP-1 signaling.

Academic Article

Abstract

  • The transmembrane glycoprotein extracellular matrix metalloproteinase inducer (EMMPRIN), and the pleiotropic proinflammatory cytokine interleukin (IL)-18, play critical roles in myocardial remodeling, by inducing matrix degrading metalloproteinases (MMPs). Previously we showed that IL-18 induces EMMPRIN expression in cardiomyocytes via MyD88/IRAK4/TRAF6/JNK-dependent Sp1 activation. Here in reciprocal studies we demonstrate that EMMPRIN is a potent inducer of IL-18 transcription, protein expression and protein secretion in primary mouse cardiomyocytes. We show for the first time that EMMPRIN stimulates the activation of NF-kappaB, AP-1, CREB, and ATF-2 in cardiomyocytes, and induces IL-18 expression via Rac1-dependent PI3K/Akt/IKK/NF-kappaB and MKK7/JNK/AP-1 signaling. Moreover, EMMPRIN induces robust time-dependent induction of various MMP mRNAs. EMMPRIN also induces the mRNA of TIMPs 1 and 3, but in a delayed fashion. These results suggest that IL-18-induced EMMPRIN expression may favor net MMP expression and ECM destruction, and thus identify both as potential therapeutic targets in countering adverse myocardial remodeling.
  • Authors

    Keywords

  • Animals, Basigin, Cells, Cultured, Enzyme-Linked Immunosorbent Assay, I-kappa B Kinase, Interleukin-18, MAP Kinase Kinase 7, Male, Mice, Mice, Inbred C57BL, Myocytes, Cardiac, NF-kappa B, Neuropeptides, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Transcription Factor AP-1, rac GTP-Binding Proteins, rac1 GTP-Binding Protein
  • Digital Object Identifier (doi)

    Author List

  • Venkatesan B; Valente AJ; Prabhu SD; Shanmugam P; Delafontaine P; Chandrasekar B
  • Start Page

  • 655
  • End Page

  • 663
  • Volume

  • 49
  • Issue

  • 4