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      Interleukin-18 stimulates fibronectin expression in primary human cardiac fibroblasts via PI3K-Akt-dependent NF-kappaB activation.

      Journal of Cellular Physiology

      Cells, Cultured, Cytokines, metabolism, Enzyme Activation, drug effects, Fibroblasts, enzymology, secretion, Fibronectins, genetics, Gene Expression Regulation, Humans, I-kappa B Kinase, Inflammation Mediators, Intercellular Signaling Peptides and Proteins, Interleukin-1 Receptor-Associated Kinases, Interleukin-18, pharmacology, Myeloid Differentiation Factor 88, Myocardium, cytology, NF-kappa B, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, RNA, Messenger, Solubility, TNF Receptor-Associated Factor 6, Transcription, Genetic

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          Abstract

          Fibronectin (FN), a key component of the extracellular matrix, is upregulated in cardiac tissue during myocardial hypertrophy and failure. Here we show that interleukin (IL)-18, a proinflammatory and pro-hypertrophic cytokine, stimulates FN expression in adult human cardiac fibroblasts (HCF), an effect blocked by either the IL-18BP:Fc chimera or IL-18 neutralizing antibodies. IL-18 stimulated FN promoter-reporter activity in HCF, a response attenuated by mutation of an NF-kappaB binding site in the FN promoter. Overexpression of p65 stimulated FN transcription. IL-18 stimulated in vitro (p65, p50) and in vivo NF-kappaB DNA binding activities, and induced kappaB-dependent reporter gene activity. These effects were inhibited by adenoviral transduction of dominant negative (dn) p65 (Ad.dnp65) and dnIKK2 (Ad.dnIKK2). Investigation of signaling intermediates revealed that IL-18 stimulated PI3 kinase activity (blocked by wortmannin, LY294002, or Ad.dnPI3Kp85), and Akt phosphorylation and kinase activity (blocked by SH-5 or Ad.dnAkt). Furthermore, targeting MyD88, IRAK1, TRAF6, PI3K, Akt, and NF-kappaB by RNA interference or dn expression vectors blunted IL-18 mediated FN transcription and mRNA expression. Conversely, FN stimulated IL-18 expression. These data provide the first evidence that IL-18 and FN stimulate each other's expression in HCF, and suggest a role for IL-18, FN and their crosstalk in myocardial hypertrophy and remodeling, disease states characterized by enhanced FN expression and fibrosis. (c) 2007 Wiley-Liss, Inc.

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          Journal
          18064631
          10.1002/jcp.21348

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