Functional redundancy of class I phosphoinositide 3-kinase (PI3K) isoforms in signaling growth factor-mediated human neutrophil survival.
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...
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Public Library of Science (PLoS)
2012-01-01
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| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0045933&type=printable |
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| author | 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 |
| author_facet | 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 |
| author_sort | Jatinder K Juss |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-b74aab3989124dae8e5cc3a0babdf320 |
| institution | OA Journals |
| issn | 1932-6203 |
| language | English |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS ONE |
| spelling | doaj-art-b74aab3989124dae8e5cc3a0babdf3202025-08-20T02:30:56ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0179e4593310.1371/journal.pone.0045933Functional redundancy of class I phosphoinositide 3-kinase (PI3K) isoforms in signaling growth factor-mediated human neutrophil survival.Jatinder K JussRichard P HayhoeCharles E OwenIan BruceSarah R WalmsleyAndrew S CowburnSuhasini KulkarniKeith B BoyleLen StephensPhillip T HawkinsEdwin R ChilversAlison M CondliffeWe 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.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0045933&type=printable |
| spellingShingle | 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 Functional redundancy of class I phosphoinositide 3-kinase (PI3K) isoforms in signaling growth factor-mediated human neutrophil survival. PLoS ONE |
| title | Functional redundancy of class I phosphoinositide 3-kinase (PI3K) isoforms in signaling growth factor-mediated human neutrophil survival. |
| title_full | Functional redundancy of class I phosphoinositide 3-kinase (PI3K) isoforms in signaling growth factor-mediated human neutrophil survival. |
| title_fullStr | Functional redundancy of class I phosphoinositide 3-kinase (PI3K) isoforms in signaling growth factor-mediated human neutrophil survival. |
| title_full_unstemmed | Functional redundancy of class I phosphoinositide 3-kinase (PI3K) isoforms in signaling growth factor-mediated human neutrophil survival. |
| title_short | Functional redundancy of class I phosphoinositide 3-kinase (PI3K) isoforms in signaling growth factor-mediated human neutrophil survival. |
| title_sort | functional redundancy of class i phosphoinositide 3 kinase pi3k isoforms in signaling growth factor mediated human neutrophil survival |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0045933&type=printable |
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