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IL-1beta induces expression of matrix metalloproteinase-9 and cell migration via a c-Src-dependent, growth factor

Ching-Yi Cheng1, Chang-Ting Kuo, Chih-Chung Lin

  • 1Department of Pharmacology, Chang Gung University, Tao-Yuan, Taiwan.

British Journal of Pharmacology
|July 24, 2010
PubMed
Abstract

Insights

Interleukin-1beta triggers cell migration and matrix metalloproteinase-9 (MMP-9) expression in A549 cells via c-Src-dependent growth factor receptor transactivation, PI3K/Akt, and NF-kappaB signaling.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Cancer Research

Background:

  • Interleukin-1beta (IL-1beta) is a key inflammatory cytokine.
  • IL-1beta regulates matrix metalloproteinase-9 (MMP-9) expression via mitogen-activated protein kinases (MAPKs) and NF-kappaB.
  • IL-1beta also activates growth factor receptor transactivation and the phosphatidylinositol 3-kinase (PI3K)/Akt pathway.

Purpose of the Study:

  • To investigate the role of growth factor receptor transactivation and PI3K/Akt signaling in IL-1beta-induced MMP-9 expression in A549 cells.
  • To elucidate the signaling pathways linking IL-1beta stimulation to MMP-9 production and cell migration.

Main Methods:

  • A549 cells were treated with pharmacological inhibitors, neutralizing antibodies, or transfected with dominant-negative mutants/siRNA.
  • Cell migration was assessed using an in vitro scratch assay.
  • MMP-9 expression, activity, and transcriptional activity were analyzed by Western blot, gelatin zymography, RT-PCR, chromatin immunoprecipitation, and promoter assays.

Main Results:

  • Inhibition of c-Src, platelet-derived growth factor (PDGF) receptor, or epidermal growth factor (EGF) receptor, and siRNA for c-Src and Akt, blocked IL-1beta-induced A549 cell migration.
  • IL-1beta induced MMP-9 expression via c-Src-dependent transactivation of EGF receptor (EGFR) and PDGF receptor (PDGFR), involving PI3K/Akt and NF-kappaB activation.
  • LY294002 attenuated IL-1beta-stimulated Akt and NF-kappaB activation and NF-kappaB recruitment to the MMP-9 promoter.

Conclusions:

  • IL-1beta-induced MMP-9 expression and A549 cell migration are mediated by c-Src-dependent transactivation of EGFR/PDGFR.
  • This pathway involves the PI3K/Akt signaling cascade, ultimately linking to NF-kappaB activation.
  • These findings reveal a critical signaling axis in IL-1beta-driven cellular processes relevant to inflammation and potentially cancer.

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