Functional Redundancy of Class I Phosphoinositide 3-Kinase (PI3K) Isoforms in Signaling Growth Factor-Mediated Human Neutrophil Survival

Jatinder K. Juss, Richard P. Hayhoe, Charles E. Owen, Ian Bruce, Sarah R. Walmsley, Andrew S. Cowburn, Suhasini Kulkarni, Keith B. Boyle, Len Stephens, Phillip T. Hawkins, Edwin R. Chilvers, Alison M. Condliffe*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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 (PI3K alpha, PI3K beta, PI3K delta, and PI3K gamma), and (iii) transgenic mice lacking functional PI3K isoforms (p110 delta(KO)gamma(KO) or p110 gamma(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 p110 delta(KO)gamma(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.

Original languageEnglish
Article numbere45933
Number of pages15
JournalPLoS ONE
Volume7
Issue number9
DOIs
Publication statusPublished - 24 Sep 2012

Keywords

  • COLONY-STIMULATING FACTOR
  • RESPIRATORY-DISTRESS-SYNDROME
  • PHOSPHATIDYLINOSITOL 3-KINASE
  • KINASE INHIBITORS
  • DISTINCT ROLES
  • CELL-SURVIVAL
  • APOPTOSIS
  • PI3K-GAMMA
  • ACTIVATION
  • GAMMA

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