TY - JOUR
T1 - Interleukin-18 stimulates fibronectin expression in primary human cardiac fibroblasts via PI3K-Akt-dependent NF-κB activation
AU - Reddy, Venkatapuram Seenu
AU - Harskamp, Ralf Egan
AU - Van Ginkel, Margreet Willie
AU - Calhoon, John
AU - Baisden, Clinton Eugene
AU - Kim, In San
AU - Valente, Anthony J.
AU - Chandrasekar, Bysani
PY - 2008/6
Y1 - 2008/6
N2 - 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 dnlKK2 (Ad.dnlKK2). 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.
AB - 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 dnlKK2 (Ad.dnlKK2). 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.
UR - http://www.scopus.com/inward/record.url?scp=42949096486&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/jcp.21348
DO - https://doi.org/10.1002/jcp.21348
M3 - Article
C2 - 18064631
SN - 0021-9541
VL - 215
SP - 697
EP - 707
JO - Journal of cellular physiology
JF - Journal of cellular physiology
IS - 3
ER -