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-kappaB activation.
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.
Reddy
Venkatapuram Seenu
VS
Cardiothoracic Surgery, University of Texas Health Science Center, San Antonio, Texas, USA.
Prabhu
Sumanth D
SD
Mummidi
Srinivas
S
Valente
Anthony J
AJ
Venkatesan
Balachandar
B
Shanmugam
Prakashsrinivasan
P
Delafontaine
Patrice
P
Chandrasekar
Bysani
B
D000818:Animals; D001483:Base Sequence; D051926:Basigin / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000378:metabolism; D007136:Immunoglobulins / Q000378:metabolism*; D020382:Interleukin-18 / Q000494:pharmacology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D008969:Molecular Sequence Data; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D020257:Ventricular Remodeling
C497887:Bsg protein, mouse; D007136:Immunoglobulins; D020382:Interleukin-18; D016328:NF-kappa B; C090698:SP1 antigen; D019715:Tissue Inhibitor of Metalloproteinase-1; D019717:Tissue Inhibitor of Metalloproteinase-3; D018808:Transcription Factor AP-1; D051926:Basigin; D048670:MAP Kinase Kinase 4; D020780:Matrix Metalloproteinase 9