Selective role of PI3K delta in neutrophil inflammatory responses

Biochem Biophys Res Commun. 2003 Sep 5;308(4):764-9. doi: 10.1016/s0006-291x(03)01480-3.


Although members of the class I phosphoinositide 3-kinases (PI3Ks) have been implicated in neutrophil inflammatory responses, the contribution of the individual PI3K isoforms in neutrophil activation has not been tractable with the non-selective inhibitors, LY294002 and wortmannin. We have developed a novel series of PI3K inhibitors that is selective for PI3K delta, an isoform expressed predominantly in hematopoietic cells. In addition to being selective between members of class I PI3Ks, representatives of these inhibitors such as IC980033 and IC87114 did not inhibit any protein kinases tested. Utilizing these inhibitors we report here a novel role for PI3K delta in neutrophil activation. Inhibition of PI3K delta with IC980033 and IC87114 blocked both fMLP- and TNF1 alpha-induced neutrophil superoxide generation and elastase exocytosis. The PI3K delta inhibitor IC87114 also blocked TNF1 alpha-stimulated elastase exocytosis from neutrophils in a mouse model of inflammation. To our knowledge, this is the first in vivo efficacy demonstration of a PI3K delta inhibitor in an animal model. Inhibition of PI3K delta, however, had no effect on in vitro neutrophil bactericidal activity and Fc gamma R-stimulated superoxide generation. Thus, PI3K delta plays an essential role in certain signaling pathways of neutrophil activation and appears to be an attractive target for the development of an anti-inflammatory therapeutic.

MeSH terms

  • Adenine / analogs & derivatives
  • Adenine / pharmacology
  • Androstadienes / pharmacology
  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Chromones / pharmacology
  • Class I Phosphatidylinositol 3-Kinases
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Exocytosis
  • Inflammation
  • Leukocyte Elastase / chemistry
  • Mice
  • Mice, Inbred BALB C
  • Morpholines / pharmacology
  • Neutrophils / enzymology*
  • Neutrophils / immunology*
  • Neutrophils / metabolism
  • Phosphatidylinositol 3-Kinases / chemistry
  • Phosphatidylinositol 3-Kinases / physiology*
  • Protein Isoforms
  • Quinazolines / pharmacology
  • Signal Transduction
  • Superoxides
  • Time Factors
  • Wortmannin


  • Androstadienes
  • Anti-Inflammatory Agents
  • Chromones
  • Enzyme Inhibitors
  • IC 87114
  • Morpholines
  • Protein Isoforms
  • Quinazolines
  • Superoxides
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Class I Phosphatidylinositol 3-Kinases
  • Pik3cd protein, mouse
  • Leukocyte Elastase
  • Adenine
  • Wortmannin