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

J Leukoc Biol. 2000 Mar;67(3):405-14. doi: 10.1002/jlb.67.3.405.

Abstract

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-beta, an autocrine co-factor for NO production. However, the addition of exogenous interferon-beta 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-beta and by a second undefined mechanism.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Androstadienes / pharmacology
  • Animals
  • Cell Line
  • Cell Membrane / drug effects
  • Cell Membrane / enzymology
  • Cell Membrane / metabolism
  • Chromones / antagonists & inhibitors
  • Chromones / pharmacology
  • Dose-Response Relationship, Drug
  • Enzyme Activation / drug effects
  • Interferon-beta / antagonists & inhibitors
  • Interferon-beta / metabolism*
  • Interferon-beta / pharmacology
  • Lipopolysaccharides / antagonists & inhibitors
  • Lipopolysaccharides / pharmacology*
  • Macrophages / cytology
  • Macrophages / drug effects*
  • Macrophages / enzymology
  • Macrophages / metabolism
  • Mice
  • Mice, Knockout
  • Morpholines / antagonists & inhibitors
  • Morpholines / pharmacology
  • Nitric Oxide / metabolism*
  • Nitrites / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Protein Kinases*
  • Protein-Tyrosine Kinases / deficiency
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism
  • Ribosomal Protein S6 Kinases / metabolism
  • Sirolimus / antagonists & inhibitors
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases
  • Tumor Necrosis Factor-alpha / metabolism
  • Wortmannin

Substances

  • Androstadienes
  • Chromones
  • Lipopolysaccharides
  • Morpholines
  • Nitrites
  • Phosphoinositide-3 Kinase Inhibitors
  • Tumor Necrosis Factor-alpha
  • Nitric Oxide
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Interferon-beta
  • Protein Kinases
  • Phosphotransferases (Alcohol Group Acceptor)
  • mTOR protein, mouse
  • Protein-Tyrosine Kinases
  • Ribosomal Protein S6 Kinases
  • TOR Serine-Threonine Kinases
  • Sirolimus
  • Wortmannin