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.
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.
Research Service, Southeast Louisiana Veterans Health Care System, New Orleans, LA 70161, USA.
Balachandar
B
Venkatesan
Anthony J
AJ
Valente
Sumanth D
SD
Prabhu
Prakashsrinivasan
P
Shanmugam
Patrice
P
Delafontaine
Bysani
B
Chandrasekar
D000818:Animals; D051926:Basigin / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D051550:I-kappa B Kinase / Q000378:metabolism*; D020382:Interleukin-18 / Q000235:genetics*; D048688:MAP Kinase Kinase 7 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D020744:rac GTP-Binding Proteins / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein
C497887:Bsg protein, mouse; D020382:Interleukin-18; D016328:NF-kappa B; D009479:Neuropeptides; C484602:Rac1 protein, mouse; D018808:Transcription Factor AP-1; D051926:Basigin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051550:I-kappa B Kinase; D048688:MAP Kinase Kinase 7; C482570:Map2k7 protein, mouse; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein