Phosphatidylinositol 3-kinase activity negatively regulates stability of cyclooxygenase 2 mRNA

J Biol Chem. 2002 Sep 6;277(36):32992-3000. doi: 10.1074/jbc.M203218200. Epub 2002 Jun 18.

Abstract

Human alveolar macrophages have both lipopolysaccharide (LPS)-induced and constitutive phosphatidylinositol 3-kinase (PI3K) activity. We observed that blocking PI3K activity increased release of prostaglandin E2 after LPS exposure, and increasing PI3K activity (interleukin-13) decreased release of prostaglandin E2 after LPS exposure. This was not because of an effect of PI3K on phospholipase 2 activity. PI3K inhibition resulted in an increase in cyclooxygenase 2 (COX2) protein, mRNA, and mRNA stability. PI3K negatively regulated activation of the p38 pathway (p38, MKK3/6, and MAPKAP2), and an active p38 was necessary for COX2 production. The data suggest that PI3K inhibition of p38 modulates COX2 expression via destabilization of LPS-induced COX2 mRNA.

Publication types

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

MeSH terms

  • Animals
  • Cells, Cultured
  • Cyclooxygenase 2
  • Dactinomycin / pharmacology
  • Dinoprostone / metabolism
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation, Enzymologic*
  • Humans
  • Interleukin-13 / pharmacology
  • Isoenzymes / genetics*
  • Isoenzymes / metabolism
  • Lipopolysaccharides / pharmacology
  • MAP Kinase Kinase 3
  • Membrane Proteins
  • Mice
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mitogen-Activated Protein Kinases / metabolism
  • Models, Biological
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Prostaglandin-Endoperoxide Synthases / genetics*
  • Prostaglandin-Endoperoxide Synthases / metabolism
  • Protein-Tyrosine Kinases / metabolism
  • RNA Stability*
  • RNA, Messenger / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Time Factors
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Enzyme Inhibitors
  • Interleukin-13
  • Isoenzymes
  • Lipopolysaccharides
  • Membrane Proteins
  • RNA, Messenger
  • Dactinomycin
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • Phosphatidylinositol 3-Kinases
  • Protein-Tyrosine Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 3
  • MAP2K3 protein, human
  • Map2k3 protein, mouse
  • Mitogen-Activated Protein Kinase Kinases
  • Dinoprostone