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IL‐1β induces proMMP‐9 expression via c‐Src‐dependent PDGFR/PI3K/Akt/p300 cascade in rat brain astrocytes
Author(s) -
Wu ChengYing,
Hsieh HsiLung,
Sun ChiChin,
Tseng ChingPing,
Yang ChuenMao
Publication year - 2008
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2008.05318.x
Subject(s) - transactivation , proto oncogene tyrosine protein kinase src , protein kinase b , pi3k/akt/mtor pathway , microbiology and biotechnology , phosphorylation , ly294002 , platelet derived growth factor receptor , biology , chromatin immunoprecipitation , cancer research , chemistry , growth factor , signal transduction , receptor , gene expression , biochemistry , promoter , gene
In a previous study, interleukin‐1β (IL‐1β) has been shown to induce matrix metalloproteinases (MMPs) expression through mitogen‐activated protein kinases and nuclear factor‐κB 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‐1β‐induced up‐regulation of proMMP‐9 was inhibited by genistein. IL‐1β 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‐1β‐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‐1β‐induced proMMP‐9 expression was blocked by pre‐treatment with curcumin (a p300 inhibitor). We further confirmed that IL‐1β 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‐1β stimulated the c‐Src‐dependent transactivation of PDGFR/PI3K/Akt cascade is independent of nuclear factor‐κB 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‐1β.