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KMID : 0578320080260010048
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Molecules and Cells
2008 Volume.26 No. 1 p.48 ~ p.52
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Raloxifene, a Selective Estrogen Receptor Modulator, Inhibits Lipopolysaccharide-induced Nitric Oxide Production by Inhibiting the Phosphatidylinositol 3-Kinase/Akt/Nuclear Factor-kappa B Pathway in RAW264.7 Macrophage Cells
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Lee Sin-Ae
Kim Byung-Chul
Park Seok-Hee
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Abstract
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We here demonstrate an anti-inflammatory action of raloxifene, a selective estrogen receptor modulator, in lipopolysaccharide (LPS)?induced murine macrophage RAW264.7 cells. Treatment with raloxifene at micromolar concentrations suppressed the production of nitric oxide (NO) by down-regulating expression of the inducible nitric oxide synthase (iNOS) gene in LPS-activated cells. The decreased expression of iNOS and subsequent reduction of NO were due to inhibition of nuclear translocation of transcription factor NF-?B. These effects were significantly inhibited by exposure to the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor, LY294002, or by expression of a dominant negative mutant of PI 3-kinase. In addition, pretreatment with raloxifene reduced LPS-induced Akt phosphorylation as well as NF-?B DNA binding activity and NF-?B-dependent reporter gene activity. Thus our findings indicate that raloxifene exerts its anti-inflammatory action in LPS-stimulated macrophages by blocking the PI 3-kinase-Akt-NF-?B signaling cascade, and eventually reduces expression of pro-inflammatory genes such as iNOS.
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KEYWORD
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anti-inflammatory, macrophages, NF-κB, nitric oxide, PI 3-kinase, raloxifene
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