Selective role of PI3K delta in neutrophil inflammatory responses.
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.
Sadhu
Chanchal
C
ICOS Corporation, 22021 20th Avenue SE, Bothell, WA 98021, USA. csadhu@icos.com
Dick
Ken
K
Tino
William T
WT
Staunton
Donald E
DE
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology; D058534:Class I Phosphatidylinositol 3-Kinases; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005089:Exocytosis; D007249:Inflammation; D019272:Leukocyte Elastase / Q000737:chemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D009025:Morpholines / Q000494:pharmacology; D009504:Neutrophils / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000502:physiology*; D020033:Protein Isoforms; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction; D013481:Superoxides; D013997:Time Factors; D000077191:Wortmannin
D000225:Adenine; D000730:Androstadienes; D000893:Anti-Inflammatory Agents; D002867:Chromones; D058534:Class I Phosphatidylinositol 3-Kinases; D004791:Enzyme Inhibitors; D019272:Leukocyte Elastase; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D020033:Protein Isoforms; D011799:Quinazolines; D013481:Superoxides; D000077191:Wortmannin; C477872:IC 87114; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C421683:Pik3cd protein, mouse