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

Venkatapuram Seenu Reddy, Ralf Egan Harskamp, Margreet Willie Van Ginkel, John Calhoon, Clinton Eugene Baisden, In-San Kim, Anthony J. Valente, Bysani Chandrasekar

Research output: Contribution to journalArticle

44 Citations (Scopus)

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-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.

Original languageEnglish
Pages (from-to)697-707
Number of pages11
JournalJournal of Cellular Physiology
Volume215
Issue number3
DOIs
Publication statusPublished - 2008 Jun 1
Externally publishedYes

Fingerprint

Interleukin-18
Fibroblasts
Phosphatidylinositol 3-Kinases
Fibronectins
Chemical activation
Transcription
Hypertrophy
TNF Receptor-Associated Factor 6
Phosphorylation
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Interleukins
Crosstalk
RNA Interference
Neutralizing Antibodies
Reporter Genes
Human Activities
Extracellular Matrix
Fibrosis
Phosphotransferases
Heart Failure

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

Cite this

Interleukin-18 stimulates fibronectin expression in primary human cardiac fibroblasts via PI3K-Akt-dependent NF-κB activation. / Reddy, Venkatapuram Seenu; Harskamp, Ralf Egan; Van Ginkel, Margreet Willie; Calhoon, John; Baisden, Clinton Eugene; Kim, In-San; Valente, Anthony J.; Chandrasekar, Bysani.

In: Journal of Cellular Physiology, Vol. 215, No. 3, 01.06.2008, p. 697-707.

Research output: Contribution to journalArticle

Reddy, VS, Harskamp, RE, Van Ginkel, MW, Calhoon, J, Baisden, CE, Kim, I-S, Valente, AJ & Chandrasekar, B 2008, 'Interleukin-18 stimulates fibronectin expression in primary human cardiac fibroblasts via PI3K-Akt-dependent NF-κB activation', Journal of Cellular Physiology, vol. 215, no. 3, pp. 697-707. https://doi.org/10.1002/jcp.21348
Reddy, Venkatapuram Seenu ; Harskamp, Ralf Egan ; Van Ginkel, Margreet Willie ; Calhoon, John ; Baisden, Clinton Eugene ; Kim, In-San ; Valente, Anthony J. ; Chandrasekar, Bysani. / Interleukin-18 stimulates fibronectin expression in primary human cardiac fibroblasts via PI3K-Akt-dependent NF-κB activation. In: Journal of Cellular Physiology. 2008 ; Vol. 215, No. 3. pp. 697-707.
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