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

Martha M Monick1, Pamela K Robeff, Noah S Butler

  • 1University of Iowa Roy J. and Lucille A. Carver College of Medicine and Veterans Administration Medical Center, Iowa City, Iowa 52242, USA. matha.monick@uiowa.edu

The Journal of Biological Chemistry
|June 20, 2002
PubMed

Insights

Blocking phosphatidylinositol 3-kinase (PI3K) activity in human macrophages increases prostaglandin E2 release by upregulating cyclooxygenase 2 (COX2) via the p38 pathway. This reveals a novel mechanism for inflammatory mediator production.

Area of Science:

  • Immunology
  • Cellular Biology
  • Molecular Biology

Background:

  • Human alveolar macrophages exhibit both lipopolysaccharide (LPS)-induced and constitutive phosphatidylinositol 3-kinase (PI3K) activity.
  • Prostaglandin E2 (PGE2) is a key inflammatory mediator released by macrophages.

Purpose of the Study:

  • To investigate the role of PI3K activity in regulating PGE2 release in human alveolar macrophages.
  • To elucidate the molecular mechanisms by which PI3K influences cyclooxygenase 2 (COX2) expression and PGE2 production.

Main Methods:

  • Pharmacological inhibition and activation of PI3K in human alveolar macrophages.
  • Stimulation with lipopolysaccharide (LPS).
  • Measurement of prostaglandin E2 release.
  • Analysis of cyclooxygenase 2 (COX2) protein and mRNA levels.
  • Investigation of the p38 mitogen-activated protein kinase (MAPK) pathway activation.

Main Results:

  • Blocking PI3K activity increased PGE2 release following LPS exposure, while PI3K activation decreased it.
  • PI3K inhibition led to increased COX2 protein, mRNA, and mRNA stability, independent of phospholipase A2 activity.
  • PI3K negatively regulated the p38 pathway, which was essential for COX2 production.

Conclusions:

  • PI3K negatively regulates COX2 expression and PGE2 release in LPS-stimulated human alveolar macrophages.
  • PI3K inhibition enhances COX2 expression by increasing mRNA stability and activating the p38 pathway.
  • These findings identify a novel PI3K-p38-COX2 signaling axis controlling inflammatory responses in macrophages.

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