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Transactivation of Src, PDGF receptor, and Akt is involved in IL-1beta-induced ICAM-1 expression in A549 cells

Chih-Chung Lin1, Chiang-Wen Lee, Tzu-Hua Chu

  • 1Department of Anesthetics, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan.

Journal of Cellular Physiology
|February 15, 2007
PubMed

Insights

Interleukin-1beta (IL-1beta) induces ICAM-1 expression via Src, PDGFR, and PI3K/Akt pathways, involving p300 transcriptional activity and histone acetylation. This pathway enhances neutrophil adhesion, which is inhibited by blocking these signaling molecules.

Area of Science:

  • Cellular and Molecular Biology
  • Immunology
  • Biochemistry

Background:

  • Interleukin-1beta (IL-1beta) is a key inflammatory cytokine.
  • IL-1beta induces ICAM-1 expression, crucial for immune cell adhesion.
  • Previous studies implicated MAPKs and NF-kappaB in IL-1beta-induced ICAM-1 expression.

Purpose of the Study:

  • To investigate the role of non-receptor tyrosine kinase (Src), PDGF receptors (PDGFRs), and PI3K/Akt pathways in IL-1beta-induced ICAM-1 expression in A549 cells.
  • To elucidate the downstream molecular mechanisms, including p300 activity and histone acetylation, involved in this process.
  • To assess the functional consequence of ICAM-1 upregulation on neutrophil adhesion.

Main Methods:

  • Reporter gene assays, Western blotting, and RT-PCR to analyze ICAM-1 expression and promoter activity.
  • Transfection with dominant-negative plasmids for Src, p85, and Akt.
  • Chromatin immunoprecipitation (ChIP) assays to determine protein-DNA interactions and histone modifications.
  • Inhibition studies using specific pathway inhibitors (PP1, AG1296, LY294002, wortmannin, SH-5, curcumin, helenalin).

Main Results:

  • Inhibitors of Src, PDGFR, PI3-K, and Akt attenuated IL-1beta-induced ICAM-1 promoter activity.
  • Dominant-negative Src, p85, and Akt significantly reduced IL-1beta-induced ICAM-1 expression.
  • IL-1beta-stimulated phosphorylation of Src, PDGFR, and Akt was abrogated by pathway inhibitors.
  • p300 inhibition blocked ICAM-1 expression, and p300 association with the ICAM-1 promoter correlated with histone H4 acetylation.
  • LY294002 inhibited the association of p300 and histone-H4 with the ICAM-1 promoter.
  • Upregulated ICAM-1 enhanced neutrophil adhesion, which was reversed by pathway inhibitors.

Conclusions:

  • Akt phosphorylation, mediated by Src/PDGFR transactivation, promotes IL-1beta-induced ICAM-1 expression in A549 cells.
  • The Src/PDGFR/PI3K/Akt pathway regulates ICAM-1 expression through p300 transcriptional coactivator activity and histone H4 acetylation.
  • Targeting these signaling pathways can inhibit IL-1beta-induced ICAM-1 expression and subsequent neutrophil adhesion.

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