title: Functional redundancy of class I phosphoinositide 3-kinase (PI3K) isoforms in signaling growth factor-mediated human neutrophil survival.
abstract: 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 (PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ), and (iii) transgenic mice lacking functional PI3K isoforms (p110δ(KO)γ(KO) or p110γ(KO)). 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 p110δ(KO)γ(KO) 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.
authors.affiliation: Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, Cambridge, United Kingdom.
authors.forename: Jatinder K
authors.initials: JK
authors.lastname: Juss
authors.forename: Richard P
authors.initials: RP
authors.lastname: Hayhoe
authors.forename: Charles E
authors.initials: CE
authors.lastname: Owen
authors.forename: Ian
authors.initials: I
authors.lastname: Bruce
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Walmsley
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Cowburn
authors.forename: Suhasini
authors.initials: S
authors.lastname: Kulkarni
authors.forename: Keith B
authors.initials: KB
authors.lastname: Boyle
authors.forename: Len
authors.initials: L
authors.lastname: Stephens
authors.forename: Phillip T
authors.initials: PT
authors.lastname: Hawkins
authors.forename: Edwin R
authors.initials: ER
authors.lastname: Chilvers
authors.forename: Alison M
authors.initials: AM
authors.lastname: Condliffe
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009504:Neutrophils / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000201:enzymology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D058534:Class I Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt