Selective role of PI3K delta in neutrophil inflammatory responses.

Abstract

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.

• Authors: Chanchal Sadhu, Ken Dick, William T Tino, Donald E Staunton
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 308 Issue 4 Pg. 764-9 (Sep 05 2003) ISSN: 0006-291X [Print] United States
• PMID: 12927784 (Publication Type: Journal Article)

Chemical References

• 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

Topics

• Adenine (analogs & derivatives, 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, immunology, metabolism)
• Phosphatidylinositol 3-Kinases (chemistry, physiology)
• Protein Isoforms
• Quinazolines (pharmacology)
• Signal Transduction
• Superoxides
• Time Factors
• Wortmannin