title: IL-1 beta induces proMMP-9 expression via c-Src-dependent PDGFR/PI3K/Akt/p300 cascade in rat brain astrocytes.
abstract: In a previous study, interleukin-1beta (IL-1beta) has been shown to induce matrix metalloproteinases (MMPs) expression through mitogen-activated protein kinases and nuclear factor-kappaB pathways in rat brain astrocytes. Moreover, transactivation of growth factor receptors and phosphatidylinositol 3-kinase (PI3K)/Akt cascade has been mentioned in the expression of several inflammatory genes. Here, we first report that IL-1beta-induced up-regulation of proMMP-9 was inhibited by genistein. IL-1beta also stimulated phosphorylation of several protein tyrosine kinases such as c-Src and platelet-derived growth factor receptor (PDGFR), which was further confirmed by western blotting using an anti-phospho-c-Src or anti-phospho-PDGFR antibody, respectively. IL-1beta-stimulated c-Src, PDGFR, and Akt phosphorylation and proMMP-9 expression were attenuated by the inhibitors of c-Src (PP1), PDGFR (AG1296), and PI3K (LY294002), respectively, or transfection with dominant negative plasmid of c-Src or short hairpin RNAs of PDGFR and Akt. Moreover, IL-1beta-induced proMMP-9 expression was blocked by pre-treatment with curcumin (a p300 inhibitor). We further confirmed that IL-1beta stimulated p300 recruitment to MMP-9 promoter, and then acetylated histone H4 by immunoprecipitation and chromatin immunoprecipitation-PCR assays. The recruitment and activation of p300 in MMP-9 promoter were inhibited by pre-treatment with PP1, AG1296, and LY294002, respectively. Moreover, IL-1beta stimulated the c-Src-dependent transactivation of PDGFR/PI3K/Akt cascade is independent of nuclear factor-kappaB pathway. These results indicated that in rat brain astrocytes cells, PI3K/Akt activation was mediated through c-Src-dependent transactivation of PDGFR promoted transcriptional co-factor p300 recruitment and activation and eventually led to increased proMMP-9 expression by IL-1beta.
authors.affiliation: Department of Physiology and Pharmacology, Chang Gung Memorial Hospital, Keelung, Taiwan.
authors.forename: Cheng-Ying
authors.initials: CY
authors.lastname: Wu
authors.forename: Hsi-Lung
authors.initials: HL
authors.lastname: Hsieh
authors.forename: Chi-Chin
authors.initials: CC
authors.lastname: Sun
authors.forename: Ching-Ping
authors.initials: CP
authors.lastname: Tseng
authors.forename: Chuen-Mao
authors.initials: CM
authors.lastname: Yang
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000201:enzymology / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D004790:Enzyme Induction / Q000502:physiology; D004792:Enzyme Precursors / Q000096:biosynthesis* / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D016391:Genes, src / Q000502:physiology*; D006801:Humans; D053583:Interleukin-1beta / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D017479:Receptors, Platelet-Derived Growth Factor / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D004792:Enzyme Precursors; D053583:Interleukin-1beta; D019869:Phosphatidylinositol 3-Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D051057:Proto-Oncogene Proteins c-akt; C120487:pro-matrix metalloproteinase 9; D020780:Matrix Metalloproteinase 9