title: Suppressive effects of anthrax lethal toxin on megakaryopoiesis.
abstract: Anthrax lethal toxin (LT) is a major virulence factor of Bacillus anthracis. LT challenge suppresses platelet counts and platelet function in mice, however, the mechanism responsible for thrombocytopenia remains unclear. LT inhibits cellular mitogen-activated protein kinases (MAPKs), which are vital pathways responsible for cell survival, differentiation, and maturation. One of the MAPKs, the MEK1/2-extracellular signal-regulated kinase pathway, is particularly important in megakaryopoiesis. This study evaluates the hypothesis that LT may suppress the progenitor cells of platelets, thereby inducing thrombocytopenic responses. Using cord blood-derived CD34(+) cells and mouse bone marrow mononuclear cells to perform in vitro differentiation, this work shows that LT suppresses megakaryopoiesis by reducing the survival of megakaryocytes. Thrombopoietin treatments can reduce thrombocytopenia, megakaryocytic suppression, and the quick onset of lethality in LT-challenged mice. These results suggest that megakaryocytic suppression is one of the mechanisms by which LT induces thrombocytopenia. These findings may provide new insights for developing feasible approaches against anthrax.
authors.affiliation: Institute of Medical Science, Tzu-Chi University, Hualien, Taiwan.
authors.forename: Po-Kong
authors.initials: PK
authors.lastname: Chen
authors.forename: Hsin-Hou
authors.initials: HH
authors.lastname: Chang
authors.forename: Guan-Ling
authors.initials: GL
authors.lastname: Lin
authors.forename: Tsung-Pao
authors.initials: TP
authors.lastname: Wang
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Lai
authors.forename: Ting-Kai
authors.initials: TK
authors.lastname: Lin
authors.forename: Ming-Chun
authors.initials: MC
authors.lastname: Hsieh
authors.forename: Jyh-Hwa
authors.initials: JH
authors.lastname: Kau
authors.forename: Hsin-Hsien
authors.initials: HH
authors.lastname: Huang
authors.forename: Hui-Ling
authors.initials: HL
authors.lastname: Hsu
authors.forename: Chi-Yuan
authors.initials: CY
authors.lastname: Liao
authors.forename: Der-Shan
authors.initials: DS
authors.lastname: Sun
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000633:toxicity*; D018952:Antigens, CD34 / Q000378:metabolism; D001427:Bacterial Toxins / Q000633:toxicity*; D016923:Cell Death / Q000187:drug effects; D005312:Fetal Blood / Q000166:cytology; D006801:Humans; D008297:Male; D008533:Megakaryocytes / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects; D013921:Thrombocytopenia / Q000139:chemically induced / Q000188:drug therapy; D013926:Thrombopoietin / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000942:Antigens, Bacterial; D018952:Antigens, CD34; D001427:Bacterial Toxins; C030325:anthrax toxin; D013926:Thrombopoietin
references.citation: Blood. 1995 Oct 1;86(7):2516-25
references.pmid: 7545460
references.citation: J Clin Invest. 1969 Jun;48(6):963-74
references.pmid: 5814231
references.citation: J Thromb Haemost. 2010 Jan;8(1):17-26
references.pmid: 19874462
references.citation: Transfusion. 2008 Dec;48(12):2638-44
references.pmid: 18798803
references.citation: J Biomed Sci. 2012 Nov 21;19:98
references.pmid: 23170801
references.citation: Blood. 2004 Jul 1;104(1):58-64
references.pmid: 15001470
references.citation: Blood. 1965 Jul;26:20-35
references.pmid: 14314398
references.citation: Cell Biol Int. 2003;27(9):769-77
references.pmid: 12972283
references.citation: Annu Rev Microbiol. 2001;55:647-71
references.pmid: 11544370
references.citation: Cell Host Microbe. 2010 Nov 18;8(5):455-62
references.pmid: 21075356
references.citation: J Biol Chem. 2008 Jun 6;283(23):15589-600
references.pmid: 18397889
references.citation: Am J Pathol. 2006 Aug;169(2):433-44
references.pmid: 16877346
references.citation: Cell Microbiol. 2005 Feb;7(2):281-92
references.pmid: 15659071
references.citation: Methods Mol Biol. 2009;482:109-26
references.pmid: 19089352
references.citation: Vet Immunol Immunopathol. 1995 Feb;44(3-4):359-68
references.pmid: 7538249
references.citation: Science. 2002 Sep 20;297(5589):2048-51
references.pmid: 12202685
references.citation: J Virol. 2007 Jun;81(11):5518-26
references.pmid: 17360740
references.citation: Pediatr Blood Cancer. 2011 Aug;57(2):199-203
references.pmid: 21337678
references.citation: Methods Mol Biol. 2012;788:291-303
references.pmid: 22130715
references.citation: Arch Pathol Lab Med. 1998 Nov;122(11):982-92
references.pmid: 9822127
references.citation: Blood. 2008 Feb 1;111(3):981-6
references.pmid: 18223171
references.citation: Infect Immun. 2004 Jan;72(1):430-9
references.pmid: 14688124
references.citation: Clin Infect Dis. 2007 Apr 1;44(7):968-71
references.pmid: 17342650
references.citation: Blood. 1987 Dec;70(6):1735-42
references.pmid: 3315039
references.citation: Lab Anim (NY). 2011 May;40(5):155-60
references.pmid: 21508954
references.citation: PLoS One. 2010 Dec 10;5(12):e14289
references.pmid: 21170330
references.citation: Blood. 2010 Dec 2;116(23):5002-9
references.pmid: 20699442
references.citation: Oncogene. 2004 Apr 12;23(16):2838-49
references.pmid: 15077147
references.citation: Nat Rev Microbiol. 2004 Sep;2(9):721-6
references.pmid: 15372082
references.citation: Haematologica. 2003 Jun;88(6):679-87
references.pmid: 12801844
references.citation: JAMA. 2002 Feb 20;287(7):858-62
references.pmid: 11851577
references.citation: Ann Hematol. 2001 May;80(5):284-91
references.pmid: 11446731
references.citation: Biochem J. 2004 Mar 1;378(Pt 2):569-77
references.pmid: 14616089
references.citation: Am J Physiol Regul Integr Comp Physiol. 2004 Apr;286(4):R699-709
references.pmid: 14715494
references.citation: Cell Cycle. 2011 May 15;10(10):1582-9
references.pmid: 21478671
references.citation: Infect Immun. 2005 Oct;73(10):7006-10
references.pmid: 16177381
references.citation: Blood. 1999 Jun 15;93(12):4222-31
references.pmid: 10361119
references.citation: Expert Rev Mol Med. 2006 Apr 11;8(7):1-18
references.pmid: 16608555
references.citation: Eur Heart J. 2001 Sep;22(17):1561-71
references.pmid: 11492985
references.citation: Nature. 2001 Nov 8;414(6860):225-9
references.pmid: 11700562
references.citation: Annu Rev Med. 2009;60:193-206
references.pmid: 19642221
references.citation: Cytokine. 2012 Jan;57(1):143-9
references.pmid: 22082805
references.citation: J Thromb Haemost. 2007 Nov;5(11):2291-9
references.pmid: 17958746
references.citation: Am J Hematol. 1997 Sep;56(1):17-25
references.pmid: 9298862
references.citation: J Clin Invest. 2003 Sep;112(5):670-82
references.pmid: 12952916
references.citation: Curr Opin Microbiol. 2004 Feb;7(1):19-24
references.pmid: 15036135
references.citation: Exp Hematol. 2012 Feb;40(2):131-42.e4
references.pmid: 22024107
references.citation: Mod Pathol. 2001 May;14(5):482-95
references.pmid: 11353060
references.citation: Cell Signal. 2001 Dec;13(12):863-75
references.pmid: 11728826
references.citation: J Infect Dis. 2012 Feb 1;205(3):453-7
references.pmid: 22158563
references.citation: Emerg Infect Dis. 2002 Oct;8(10):1019-28
references.pmid: 12396909
references.citation: Exp Cell Res. 1999 Aug 1;250(2):387-400
references.pmid: 10413593
references.citation: Blood. 2007 May 15;109(10):4229-36
references.pmid: 17244674
references.citation: Exp Hematol. 2002 Oct;30(10):1185-92
references.pmid: 12384150
references.citation: JAMA. 2002 Feb 20;287(7):869-74
references.pmid: 11851579
references.citation: Aviat Space Environ Med. 2011 Jul;82(7):699-703
references.pmid: 21748908
references.citation: J Clin Invest. 2005 Dec;115(12):3348-54
references.pmid: 16322779
references.citation: Pathophysiol Haemost Thromb. 2003 Sep-2004 Dec;33(5-6):413-6
references.pmid: 15692253
references.citation: Chest. 2003 Nov;124(5):1956-67
references.pmid: 14605073
references.citation: Blood. 2003 Apr 1;101(7):2609-16
references.pmid: 12468435
references.citation: PLoS One. 2009;4(1):e4167
references.pmid: 19132100
references.citation: J Cell Physiol. 2002 Jan;190(1):7-20
references.pmid: 11807806
references.citation: Proc Natl Acad Sci U S A. 2003 Apr 29;100(9):5170-4
references.pmid: 12700348
references.citation: FEMS Immunol Med Microbiol. 2008 Dec;54(3):309-18
references.pmid: 19049643
references.citation: Exp Hematol. 2001 Dec;29(12):1425-31
references.pmid: 11750101
references.citation: J Infect Dis. 2005 Oct 15;192(8):1465-74
references.pmid: 16170766
references.citation: Emerg Infect Dis. 2001 Nov-Dec;7(6):933-44
references.pmid: 11747719