Central role for G protein-coupled phosphoinositide 3-kinase gamma in inflammation

Science. 2000 Feb 11;287(5455):1049-53. doi: 10.1126/science.287.5455.1049.

Abstract

Phosphoinositide 3-kinase (PI3K) activity is crucial for leukocyte function, but the roles of the four receptor-activated isoforms are unclear. Mice lacking heterotrimeric guanine nucleotide-binding protein (G protein)-coupled PI3Kgamma were viable and had fully differentiated neutrophils and macrophages. Chemoattractant-stimulated PI3Kgamma-/- neutrophils did not produce phosphatidylinositol 3,4,5-trisphosphate, did not activate protein kinase B, and displayed impaired respiratory burst and motility. Peritoneal PI3Kgamma-null macrophages showed a reduced migration toward a wide range of chemotactic stimuli and a severely defective accumulation in a septic peritonitis model. These results demonstrate that PI3Kgamma is a crucial signaling molecule required for macrophage accumulation in inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chemotactic Factors / pharmacology
  • Chemotaxis*
  • Chemotaxis, Leukocyte / physiology
  • Enzyme Activation
  • Gene Targeting
  • Heterotrimeric GTP-Binding Proteins / metabolism*
  • Isoenzymes / metabolism
  • Macrophages, Peritoneal / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neutrophils / metabolism
  • Neutrophils / physiology*
  • Peritonitis / enzymology
  • Peritonitis / immunology*
  • Peritonitis / pathology
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphatidylinositol Phosphates / metabolism
  • Protein Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Respiratory Burst
  • Signal Transduction*

Substances

  • Chemotactic Factors
  • Isoenzymes
  • Phosphatidylinositol Phosphates
  • Proto-Oncogene Proteins
  • phosphatidylinositol 3,4,5-triphosphate
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Heterotrimeric GTP-Binding Proteins