Phosphatidyl inositol 3-kinase and mTOR mediate lipopolysaccharide-stimulated nitric oxide production in macrophages via interferon-beta

Bacterial lipopolysaccharide (LPS) elicits responses by macrophages that he lp the body repel infections. Recent evidence indicates that phosphatidylin ositol 3-kinase (PI 3-kinase) may mediate some of these responses. Here, we show that exposing macrophages to LPS rapidly increased membrane-associate d 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 p 70 S6 kinase activation, implying that this kinase is controlled by PI 3-ki nase and mTOR, These inhibitors also substantially reduced LPS-induced nitr ic oxide (NO) production, This inhibition was, in part, attributable to imp aired LPS-stimulated secretion of interferon-beta, an autocrine co-factor f or NO production, However, the addition of exogenous interferon-beta did no t fully restore NO production, indicating that the NO response was being in hibited by another mechanism as well. Together, these data suggest that PI 3-kinase, mTOR, and possibly p70 S6 kinase mediate LPS-induced NO productio n by regulating the secretion of interferon-beta and by a second undefined mechanism.