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Instituto de Bioquímica (Centro Mixto Consejo Superior de Investigaciones Cientificas-Universidad Compluteuse de Madrid, Facultad de Farmacia, Universidad Complutense, Madrid, Spain The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Triggering of the macrophage cell line RAW 264.7 with LPS promotes
a transient activation of phosphatidylinositol 3-kinase (PI3-kinase).
Incubation of activated macrophages with wortmannin and LY294002, two
inhibitors of PI3-kinase, increased the amount of inducible nitric
oxide synthase (iNOS) and the synthesis of nitric oxide. Treatment with
wortmannin promoted a prolonged activation of NF-
B in LPS-treated
cells as well as an increase in the promoter activity of the iNOS gene
as deduced from transfection experiments using a 1.7-kb fragment of the
5' flanking region of the iNOS gene. Cotransfection of cells with a
catalytically active p110 subunit of PI3-kinase impaired the
responsiveness of the iNOS promoter to LPS stimulation, whereas
transfection with a kinase-deficient mutant of p110 maintained the
up-regulation in response to wortmannin. These results indicate that
PI3-kinase plays a negative role in the process of macrophage
activation and suggest that this enzyme might participate in the
mechanism of action of antiinflammatory
cytokines.
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