Functional Redundancy of Class I Phosphoinositide 3-Kinase PI3K Isoforms in Signaling Growth Factor-Mediated Human Neutrophil SurvivalReport as inadecuate




Functional Redundancy of Class I Phosphoinositide 3-Kinase PI3K Isoforms in Signaling Growth Factor-Mediated Human Neutrophil Survival - Download this document for free, or read online. Document in PDF available to download.

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 p110δKOγKO or p110γKO. 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 p110δKOγKO 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.



Author: Jatinder K. Juss, Richard P. Hayhoe, Charles E. Owen, Ian Bruce, Sarah R. Walmsley, Andrew S. Cowburn, Suhasini Kulkarni, Keith B

Source: http://plos.srce.hr/



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