Although members of the class I phosphomositide 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 PI3Kdelta, 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 PI3Kdelta in neutrophil activation. Inhibition of PI3Kdelta with IC980033 and IC87114 blocked both fMLP-and TNF1alpha-induced neutrophil superoxide generation and elastase exocytosis. The PI3Kdelta inhibitor IC87114 also blocked TNF1alpha-stimulated elastase exocytosis from neutrophils in a mouse model of inflammation. To our knowledge, this is the first in vivo efficacy demonstration of a PI3Kdelta inhibitor in an animal model. Inhibition of PI3Kdelta, however, had no effect on in vitro neutrophil bactericidal activity and FcyR-stimulated superoxide generation. Thus, PI3Kdelta 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. (C) 2003 Elsevier Inc. All rights reserved.