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pubmed-article:12046690pubmed:abstractTextThe mechanism by which lipopolysaccharide (LPS) or phorbol 12-myristate 13-acetate (PMA) induces production of proinflammatory cytokines in murine macrophages, and the role of phosphatidylinositol 3-kinase (PI3-kinase) have not been well investigated. Activation of nuclear factor kappaB (NF-kappaB) is initiated by the phosphorylation of the inhibitory subunit, IkappaB, which targets IkappaB for degradation and leads to the release of active NF-kappaB. In this study we demonstrate that 2-(4-morpholinyl)-8-phenylchromone (LY294002), which inhibits PI3-kinase, specifically inhibited degradation of IkappaBalpha in RAW264.7 cells stimulated with interferon-gamma (IFN-gamma) plus LPS or IFN-gamma plus PMA. To elucidate the importance of this activity in RAW264.7 cells, we examined tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-6 production in the activated cells. Pretreatment of the cells with LY294002 resulted in the inhibition of TNF-alpha and IL-6 production in RAW264.7 cells stimulated with IFN-gamma plus LPS or IFN-gamma plus PMA. Furthermore, LY294002 inhibited the production of nitric oxide (NO) in RAW264.7 cells stimulated with IFN-gamma plus LPS or IFN-gamma plus PMA. LY294002 also inhibited inducible NO synthase (iNOS) mRNA expression in the activated RAW264.7 cells. In conclusion, the present results suggest that PI3-kinase is involved in the signal transduction pathway responsible for LPS- or PMA-mediated TNF-alpha and IL-6 production, and that LY294002 inhibits NO generation through blocking the degradation of IkappaBalpha in activated RAW264.7 cells.lld:pubmed
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pubmed-article:12046690pubmed:authorpubmed-author:HSUF JFJlld:pubmed
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pubmed-article:12046690pubmed:dateRevised2010-11-18lld:pubmed
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pubmed-article:12046690pubmed:articleTitleDegradation of IkappaBalpha in activated RAW264.7 cells is blocked by the phosphatidylinositol 3-kinase inhibitor LY294002.lld:pubmed
pubmed-article:12046690pubmed:affiliationDepartment of Oriental Pharmacy, Korea Institute of Oriental Pharmacy, College of Pharmacy, Wonkwang University, Chonbuk.lld:pubmed
pubmed-article:12046690pubmed:publicationTypeJournal Articlelld:pubmed
pubmed-article:12046690pubmed:publicationTypeResearch Support, Non-U.S. Gov'tlld:pubmed
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