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Interleukin‐18 stimulates fibronectin expression in primary human cardiac fibroblasts via PI3K‐Akt‐dependent NF‐κB activation

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‐κB binding site in the FN promoter. Overexpression of p65 stimulated FN transcription. IL‐18 stimulated in vitro (p65, p50) and in vivo NF‐κB DNA binding activities, and induced κB‐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‐κB 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. J. Cell. Physiol. 215: 697–707, 2008. © 2007 Wiley‐Liss, Inc.