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Phosphatidylinositol 3‐kinase and mTOR mediate lipopolysaccharide‐stimulated nitric oxide production in macrophages via interferon‐β
Author(s) -
Weinstein Steven L.,
Finn Alexander J.,
Davé Shaival H.,
Meng Fanying,
Lowell Clifford A.,
Sanghera Jasbinder S.,
DeFranco Anthony L.
Publication year - 2000
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1002/jlb.67.3.405
Subject(s) - p70 s6 kinase 1 , phosphatidylinositol , biology , kinase , pi3k/akt/mtor pathway , microbiology and biotechnology , nitric oxide , signal transduction , endocrinology
Bacterial lipopolysaccharide (LPS) elicits responses by macrophages that help the body repel infections. Recent evidence indicates that phosphatidylinositol 3‐kinase (PI 3‐kinase) may mediate some of these responses. Here, we show that exposing macrophages to LPS rapidly increased membrane‐associated PI 3‐kinase activity and also elevated p70 S6 kinase activity. Inhibitors of PI 3‐kinase or the mammalian target of rapamycin (mTOR) fully blocked p70 S6 kinase activation, implying that this kinase is controlled by PI 3‐kinase and mTOR. These inhibitors also substantially reduced LPS‐induced nitric oxide (NO) production. This inhibition was, in part, attributable to impaired LPS‐stimulated secretion of interferon‐β, an autocrine co‐factor for NO production. However, the addition of exogenous interferon‐β did not fully restore NO production, indicating that the NO response was being inhibited by another mechanism as well. Together, these data suggest that PI 3‐kinase, mTOR, and possibly p70 S6 kinase mediate LPS‐induced NO production by regulating the secretion of interferon‐β and by a second undefined mechanism. J. Leukoc. Biol. 67: 405–414; 2000.