LY294002 inhibits LPS-induced NO production through a inhibition of NF-кB activation: independent mechanism of phosphatidylinositol 3-kinase

Abstract

Phosphatidylinositol 3-kinase (PI3K) is critical player in cell proliferation and survival. The effects of LY294002 andwortmannin, inhibitors of PI3K, on nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) expression in lipoploysaccharide (LPS)-induced Raw264.7 cells were investigated. Significant inhibition of LPS-induced protein kinase B (PKB, Akt) phosphorylation occurred at 25 M LY294002 or 0.5 Mwortmannin. At the same concentrations, LY294002, but not wortmannin, significantly inhibited NO production and iNOS expression. LY303511, an inactive analogue of LY294002, also inhibited NO production and iNOS expression. In addition, LY294002 and LY303511 significantly inhibited theDNAbinding activity of NF- Band NF- Bdependent reporter gene expression. These results suggest that LY294002 inhibits iNOS expression at least in part via inhibition of NF- B activation, independent of PI3K. © 2004 Elsevier B.V. All rights reserved. Keywords: Nitric oxide (NO); Inducible nitric oxide synthase (iNOS); LY294002; Phosphatidylinositol 3-kinase (PI3K); NF- B; Lipoploysaccharide