Involvement of phosphatidylinositol 3-kinase gamma in neutrophil apoptosis.
Although phosphoinositide 3-kinases (PI3-K) are known to participate in anti-apoptotic pathways, their importance in modulating neutrophil apoptosis in vivo has not been examined. In these studies, we used neutrophils from mice lacking the PI3-Kgamma isoform (PI3-Kgamma-/-) to determine the role that PI3-Kgamma occupies in neutrophil apoptosis under in vivo conditions. We found that neutrophil apoptosis under basal and LPS-stimulated conditions was increased in PI3-Kgamma-/- mice compared to that present in control PI3-Kgamma+/+ animals. Neutrophils from PI3-Kgamma-/- mice demonstrated decreased amounts of active, serine 473 phosphorylated Akt, phosphorylated CREB, and diminished nuclear translocation of NF-kappaB. Levels of the CREB-dependent anti-apoptotic protein Mcl-1 and of the NF-kappaB-dependent anti-apoptotic mediator Bcl-x(L) were significantly decreased in PI3-Kgamma-/- neutrophils. In contrast, PI3-Kgamma-/- neutrophils contained diminished amounts of phosphorylated, inactive forms of the pro-apoptotic mediators, Bad, FKHR, and GSK-3beta. These results demonstrate that PI3-Kgamma directly participates in multiple in vivo pathways involved in regulating neutrophil apoptosis.
Yang
Kuang-Yao
KY
Chest Department, Taipei Veterans General Hospital, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
Arcaroli
John
J
Kupfner
John
J
Pitts
Todd M
TM
Park
Jong Sung
JS
Strasshiem
Derek
D
Perng
Reury-Perng
RP
Abraham
Edward
E
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002352:Carrier Proteins / Q000378:metabolism; D058544:Class Ib Phosphatidylinositol 3-Kinase; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology* / Q000201:enzymology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051025:bcl-Associated Death Protein
D002352:Carrier Proteins; D058544:Class Ib Phosphatidylinositol 3-Kinase; D017362:Cyclic AMP Response Element-Binding Protein; D007527:Isoenzymes; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D051025:bcl-Associated Death Protein; C494820:Bad protein, mouse; C579094:Mcl1 protein, mouse; C546764:Pik3cg protein, mouse