%0 Journal Article
%T Functional Redundancy of Class I Phosphoinositide 3-Kinase (PI3K) Isoforms in Signaling Growth Factor-Mediated Human Neutrophil Survival
%A Jatinder K. Juss
%A Richard P. Hayhoe
%A Charles E. Owen
%A Ian Bruce
%A Sarah R. Walmsley
%A Andrew S. Cowburn
%A Suhasini Kulkarni
%A Keith B. Boyle
%A Len Stephens
%A Phillip T. Hawkins
%A Edwin R. Chilvers
%A Alison M. Condliffe
%J PLOS ONE
%D 2012
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0045933
%X We have investigated the contribution of individual phosphoinositide 3-kinase (PI3K) Class I isoforms to the regulation of neutrophil survival using (i) a panel of commercially available small molecule isoform-selective PI3K Class I inhibitors, (ii) novel inhibitors, which target single or multiple Class I isoforms (PI3K¦Á, PI3K¦Â, PI3K¦Ä, and PI3K¦Ã), and (iii) transgenic mice lacking functional PI3K isoforms (p110¦ÄKO¦ÃKO or p110¦ÃKO). Our data suggest that there is considerable functional redundancy amongst Class I PI3Ks (both Class IA and Class IB) with regard to GM-CSF-mediated suppression of neutrophil apoptosis. Hence pharmacological inhibition of any 3 or more PI3K isoforms was required to block the GM-CSF survival response in human neutrophils, with inhibition of individual or any two isoforms having little or no effect. Likewise, isolated blood neutrophils derived from double knockout PI3K p110¦ÄKO¦ÃKO mice underwent normal time-dependent constitutive apoptosis and displayed identical GM-CSF mediated survival to wild type cells, but were sensitized to pharmacological inhibition of the remaining PI3K isoforms. Surprisingly, the pro-survival neutrophil phenotype observed in patients with an acute exacerbation of chronic obstructive pulmonary disease (COPD) was resilient to inactivation of the PI3K pathway.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0045933