BACKGROUND AND PURPOSE: Interleukin (IL)-1beta-induced matrix metalloproteinase (MMP-9) expression is regulated by mitogen activated protein kinases (MAPKs) and NF-kappaB. IL-1beta 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-1beta-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-1beta. 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-1beta-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-1beta-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-1beta-stimulated activation and translocation of Akt and NF-kappaB (p65); the recruitment of activated NF-kappaB (p65) to the MMP-9 promoter region was attenuated by LY294002. CONCLUSIONS AND IMPLICATIONS: IL-1beta-induced MMP-9 expression and cell migration was mediated through c-Src-dependent transactivation of EGFR/PDGFR/PI3K/Akt linking to the NF-kappaB pathway in A549 cells.
BACKGROUND AND PURPOSE: Interleukin (IL)-1beta-induced matrix metalloproteinase (MMP-9) expression is regulated by mitogen activated protein kinases (MAPKs) and NF-kappaB. IL-1beta 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-1beta-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-1beta. 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-1beta-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-1beta-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-1beta-stimulated activation and translocation of Akt and NF-kappaB (p65); the recruitment of activated NF-kappaB (p65) to the MMP-9 promoter region was attenuated by LY294002. CONCLUSIONS AND IMPLICATIONS: IL-1beta-induced MMP-9 expression and cell migration was mediated through c-Src-dependent transactivation of EGFR/PDGFR/PI3K/Akt linking to the NF-kappaB pathway in A549 cells.
Authors: Jasti S Rao; Christopher Gondi; Chandramu Chetty; Subramanyam Chittivelu; Pushpa A Joseph; Sajani S Lakka Journal: Mol Cancer Ther Date: 2005-09 Impact factor: 6.261
Authors: Tetsuya Homma; Atsushi Kato; Masafumi Sakashita; Tetsuji Takabayashi; James E Norton; Lydia A Suh; Roderick G Carter; Kathleen E Harris; Anju T Peters; Leslie C Grammer; Jin-Young Min; Stephanie Shintani-Smith; Bruce K Tan; Kevin Welch; David B Conley; Robert C Kern; Robert P Schleimer Journal: Am J Respir Cell Mol Biol Date: 2017-09 Impact factor: 6.914
Authors: F M S Gurgis; Y T Yeung; M X M Tang; B Heng; M Buckland; A J Ammit; J Haapasalo; H Haapasalo; G J Guillemin; T Grewal; L Munoz Journal: Oncogene Date: 2014-08-04 Impact factor: 9.867