BACKGROUND AND PURPOSE Interleukin (IL)‐1β‐induced matrix metalloproteinase (MMP‐9) expression is regulated by mitogen activated protein kinases (MAPKs) and NF‐κB. IL‐1β also stimulates transactivation of growth factor receptors and phosphatidylinositol 3‐kinase (PI3K)/Akt., leading to the expression of inflammatory proteins. Here, we investigated whether these transactivation mechanisms participated in IL‐1β‐induced MMP‐9 expression in A549 cells.

EXPERIMENTAL APPROACH A549 cells were treated with/without pharmacological inhibitors and neutralizing antibody or transfected with dominant negative mutants and siRNA of particular protein kinases before stimulation with IL‐1β. Cell migration was measured by in vitro scratch assay. Expression and enzymatic activity of MMP‐9 were analysed by Western blot and gelatin zymography. Transcriptional activity of MMP‐9 was analysed by RT‐PCR, chromatin immunoprecipitation and promoter assays.

KEY RESULTS Inhibition of MMP‐9 expression by inhibitors of Src (PP1), platelet‐derived growth factor (PDGF) receptor and epithelial growth factor (EGF) receptor or transfection with siRNA for Src and Akt prevented IL‐1β‐induced migration of A549 cells. These tyrosine kinases were involved through phosphorylation of Src, PDGF, or EGF receptors (EGFRs) via the formation of Src/PDGFR or Src/EGFR complexes, attenuated by PP1. IL‐1β‐induced MMP‐9 expression through EGFR transactivation was diminished by inhibitors of MMPs and heparin‐binding EGF‐like factor (HB‐EGF), or a neutralizing HB‐EGF antibody. IL‐1β‐stimulated activation and translocation of Akt and NF‐κB (p65); the recruitment of activated NF‐κB (p65) to the MMP‐9 promoter region was attenuated by LY294002.

CONCLUSIONS AND IMPLICATIONS IL‐1β‐induced MMP‐9 expression and cell migration was mediated through c‐Src‐dependent transactivation of EGFR/PDGFR/PI3K/Akt linking to the NF‐κB pathway in A549 cells.