title: G-CSF activation of AKT is not sufficient to prolong neutrophil survival.
abstract: Neutrophils play an important role in the innate immune response against bacterial and fungal infections. They have a short lifespan in circulation, and their survival can be modulated by several cytokines, including G-CSF. Previous studies have implicated AKT as a critical signaling intermediary in the regulation of neutrophil survival. Our results demonstrate that G-CSF activation of AKT is not sufficient to prolong neutrophil survival. Neutrophils treated with G-CSF undergo apoptosis, even in the presence of high levels of p-AKT. In addition, inhibitors of AKT and downstream targets failed to alter neutrophil survival. In contrast, neutrophil precursors appear to be dependent on AKT signaling pathways for survival, whereas high levels of p-AKT inhibit proliferation. Our data suggest that the AKT/mTOR pathway, although important in G-CSF-driven myeloid differentiation, proliferation, and survival of early hematopoietic progenitors, is less essential in G-CSF suppression of neutrophil apoptosis. Whereas basal AKT levels may be required for the brief life of neutrophils, further p-AKT expression is not able to extend the neutrophil lifespan in the presence of G-CSF.
authors.affiliation: Winship Cancer Institute, Department of Hematology and Oncology, Emory University, Atlanta, GA 30322, USA. lsouza@emory.edu
authors.forename: Liliana R
authors.initials: LR
authors.lastname: Souza
authors.forename: Erica
authors.initials: E
authors.lastname: Silva
authors.forename: Elissa
authors.initials: E
authors.lastname: Calloway
authors.forename: Carlos
authors.initials: C
authors.lastname: Cabrera
authors.forename: Morgan L
authors.initials: ML
authors.lastname: McLemore
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D005434:Flow Cytometry; D016179:Granulocyte Colony-Stimulating Factor / Q000276:immunology / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D018375:Neutrophil Activation / Q000187:drug effects / Q000276:immunology*; D009504:Neutrophils / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology
chemical_list: D016179:Granulocyte Colony-Stimulating Factor; D051057:Proto-Oncogene Proteins c-akt
keywords: apoptosis; granulocyte colony-stimulating factor; granulocytes; mTOR; protein kinase B
references.citation: Immun Ageing. 2005 Mar 02;2(1):6
references.pmid: 15743527
references.citation: Trends Immunol. 2011 Mar;32(3):117-24
references.pmid: 21317039
references.citation: Eur J Immunol. 2002 Feb;32(2):486-93
references.pmid: 11828365
references.citation: Blood. 1992 Oct 15;80(8):2012-20
references.pmid: 1382715
references.citation: Mol Biol Cell. 2012 Apr;23(7):1219-30
references.pmid: 22323291
references.citation: Blood. 2010 Feb 18;115(7):1406-15
references.pmid: 20008787
references.citation: Nat Rev Cancer. 2006 Mar;6(3):184-92
references.pmid: 16453012
references.citation: J Immunol. 2003 Jul 15;171(2):1035-41
references.pmid: 12847277
references.citation: Blood. 2010 May 27;115(21):4237-46
references.pmid: 20332370
references.citation: Blood. 2008 Jan 1;111(1):112-21
references.pmid: 17890457
references.citation: EMBO J. 1996 Dec 2;15(23):6541-51
references.pmid: 8978681
references.citation: Blood. 2006 Mar 1;107(5):1847-56
references.pmid: 16282349
references.citation: Stem Cells. 2006 Jan;24(1):105-14
references.pmid: 16123382
references.citation: Blood. 2010 Jul 29;116(4):625-7
references.pmid: 20410504
references.citation: Blood. 2006 Oct 15;108(8):2562-8
references.pmid: 16772601
references.citation: Blood. 2010 May 20;115(20):4030-8
references.pmid: 20354168
references.citation: Immunity. 2001 Feb;14(2):193-204
references.pmid: 11239451
references.citation: Blood. 2011 Apr 7;117(14):3881-92
references.pmid: 21292774
references.citation: Nature. 1995 Aug 17;376(6541):599-602
references.pmid: 7637810
references.citation: Cell Death Differ. 2004 Jul;11 Suppl 1:S37-44
references.pmid: 15243580
references.citation: Fiziol Zh. 2010;56(5):115-24
references.pmid: 21261133
references.citation: J Immunol. 1999 Jun 15;162(12):7002-9
references.pmid: 10358141
references.citation: FEBS J. 2007 Dec;274(23):6025-36
references.pmid: 17949438
references.citation: Apoptosis. 2000 Nov;5(5):451-8
references.pmid: 11256888
references.citation: J Clin Invest. 1998 Aug 1;102(3):483-92
references.pmid: 9691084
references.citation: Curr Protoc Immunol. 2001 May;Chapter 7:Unit 7.23
references.pmid: 18432834
references.citation: Surgery. 2001 Aug;130(2):242-8
references.pmid: 11490356
references.citation: Cancer Res. 2007 Jul 1;67(13):6238-46
references.pmid: 17616681
references.citation: Am J Hematol. 2008 Apr;83(4):288-95
references.pmid: 17924549
references.citation: J Leukoc Biol. 2009 Nov;86(5):1135-44
references.pmid: 19605699
references.citation: J Leukoc Biol. 2003 May;73(5):591-9
references.pmid: 12714573
references.citation: J Cell Biol. 1996 May;133(4):895-910
references.pmid: 8666673
references.citation: J Immunol. 2005 Sep 15;175(6):4091-102
references.pmid: 16148159
references.citation: J Immunol. 2010 Jun 15;184(12):6600-11
references.pmid: 20488790
references.citation: J Cell Physiol. 2011 Mar;226(3):822-31
references.pmid: 20857426
references.citation: Immunity. 2002 Oct;17(4):413-23
references.pmid: 12387736
references.citation: Curr Protoc Immunol. 2001 May;Chapter 10:Unit 10.17C
references.pmid: 18432682
references.citation: Blood. 2008 Sep 1;112(5):2046-54
references.pmid: 18524991
references.citation: Proc Natl Acad Sci U S A. 2010 Feb 16;107(7):2950-5
references.pmid: 20133633
references.citation: Neuro Oncol. 2010 May;12(5):434-43
references.pmid: 20406894
references.citation: Blood. 2005 Nov 1;106(9):3020-7
references.pmid: 16037394
references.citation: Blood. 2006 Mar 15;107(6):2303-10
references.pmid: 16282343
references.citation: J Clin Invest. 1989 Mar;83(3):865-75
references.pmid: 2921324
references.citation: Cell Signal. 2003 Feb;15(2):225-33
references.pmid: 12464394
references.citation: J Leukoc Biol. 2005 Dec;78(6):1408-18
references.pmid: 16204629
references.citation: J Infect Dis. 1998 Sep;178(3):891-5
references.pmid: 9728567
references.citation: J Leukoc Biol. 2009 Mar;85(3):497-507
references.pmid: 19095734
references.citation: Science. 2004 Mar 5;303(5663):1477-8
references.pmid: 15001765
references.citation: FEBS Lett. 2003 Aug 28;550(1-3):94-100
references.pmid: 12935893
references.citation: J Biol Chem. 2004 Jun 25;279(26):26915-21
references.pmid: 15078892
references.citation: J Leukoc Biol. 2002 Nov;72(5):1020-6
references.pmid: 12429725
references.citation: Proc Natl Acad Sci U S A. 2006 Oct 3;103(40):14836-41
references.pmid: 16988010
references.citation: FASEB J. 2008 Sep;22(9):3111-9
references.pmid: 18509199
references.citation: J Immunol. 2003 Dec 15;171(12):6846-55
references.pmid: 14662891
references.citation: Immunity. 1999 Aug;11(2):153-61
references.pmid: 10485650
references.citation: Cell Calcium. 2006 Jul;40(1):1-10
references.pmid: 16678897
references.citation: Proc Natl Acad Sci U S A. 2010 Oct 5;107(40):17298-303
references.pmid: 20855612