title: Herpesvirus entry mediator regulates hypoxia-inducible factor-1α and erythropoiesis in mice.
abstract: Erythropoiesis, the production of red blood cells, must be tightly controlled to ensure adequate oxygen delivery to tissues without causing thrombosis or stroke. Control of physiologic and pathologic erythropoiesis is dependent predominantly on erythropoietin (EPO), the expression of which is regulated by hypoxia-inducible factor (HIF) activity in response to low oxygen tension. Accumulating evidence indicates that oxygen-independent mediators, including inflammatory stimuli, cytokines, and growth factors, also upregulate HIF activity, but it is unclear whether these signals also result in EPO production and erythropoiesis in vivo. Here, we found that signaling through herpesvirus entry mediator (HVEM), a molecule of the TNF receptor superfamily, promoted HIF-1α activity in the kidney and subsequently facilitated renal Epo production and erythropoiesis in vivo under normoxic conditions. This Epo upregulation was mediated by increased production of NO by renal macrophages. Hvem-deficient mice displayed impaired Epo expression and aggravated anemia in response to erythropoietic stress. These data reveal that HVEM signaling functions to promote HIF-1α activity and Epo production, and thus to regulate erythropoiesis. Furthermore, our findings suggest that this molecular mechanism could represent a therapeutic target for Epo-responsive diseases, including anemia.
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore, Maryland, USA.
authors.forename: Yukimi
authors.initials: Y
authors.lastname: Sakoda
authors.forename: Sudarshan
authors.initials: S
authors.lastname: Anand
authors.forename: Yuming
authors.initials: Y
authors.lastname: Zhao
authors.forename: Jang-June
authors.initials: JJ
authors.lastname: Park
authors.forename: Yingjia
authors.initials: Y
authors.lastname: Liu
authors.forename: Atsuo
authors.initials: A
authors.lastname: Kuramasu
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
authors.forename: Scott E
authors.initials: SE
authors.lastname: Strome
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Hancock
authors.forename: Lieping
authors.initials: L
authors.lastname: Chen
authors.forename: Koji
authors.initials: K
authors.lastname: Tamada
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D015687:Cell Hypoxia; D004920:Erythropoiesis / Q000502:physiology*; D004921:Erythropoietin / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis* / Q000235:genetics; D007668:Kidney / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000502:physiology; D010100:Oxygen / Q000502:physiology; D011828:Radiation Chimera; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000911:Antibodies, Monoclonal; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053240:Receptors, Tumor Necrosis Factor, Member 14; C506029:Tnfrsf14 protein, mouse; D004921:Erythropoietin; D009569:Nitric Oxide; D010100:Oxygen
references.citation: Nat Rev Cancer. 2003 Oct;3(10):721-32
references.pmid: 13130303
references.citation: Genes Dev. 2001 Oct 15;15(20):2675-86
references.pmid: 11641274
references.citation: Blood. 2005 Apr 15;105(8):3133-40
references.pmid: 15626745
references.citation: J Clin Invest. 2005 Jul;115(7):1806-15
references.pmid: 16007254
references.citation: J Clin Invest. 1993 Sep;92(3):1587-91
references.pmid: 8397229
references.citation: Exp Cell Res. 2009 Jul 1;315(11):1791-7
references.pmid: 19332053
references.citation: Proc Natl Acad Sci U S A. 2001 Aug 14;98(17):9630-5
references.pmid: 11504942
references.citation: Cell Mol Life Sci. 2009 Nov;66(22):3539-54
references.pmid: 19756382
references.citation: Nat Rev Immunol. 2009 Sep;9(9):609-17
references.pmid: 19704417
references.citation: Blood. 2010 Nov 18;116(20):4045-59
references.pmid: 20974674
references.citation: J Immunol. 2000 Apr 15;164(8):4105-10
references.pmid: 10754304
references.citation: Nat Med. 2000 Mar;6(3):283-9
references.pmid: 10700230
references.citation: Exp Biol Med (Maywood). 2003 Jan;228(1):1-14
references.pmid: 12524467
references.citation: Blood. 2008 May 15;111(10):5223-32
references.pmid: 18202227
references.citation: Nat Genet. 2002 Dec;32(4):614-21
references.pmid: 12415268
references.citation: Annu Rev Immunol. 1997;15:323-50
references.pmid: 9143691
references.citation: Kidney Int. 2009 Apr;75(7):682-8
references.pmid: 19165176
references.citation: J Biol Chem. 1998 Oct 16;273(42):27548-56
references.pmid: 9765287
references.citation: Blood. 2011 Mar 24;117(12):3435-44
references.pmid: 21177435
references.citation: J Biol Chem. 2004 Jan 23;279(4):2550-8
references.pmid: 14600153
references.citation: Cardiovasc Res. 2007 Jul 15;75(2):275-82
references.pmid: 17412315
references.citation: Physiol Rev. 1992 Apr;72(2):449-89
references.pmid: 1557429
references.citation: Blood. 2007 May 1;109(9):4097-104
references.pmid: 17179227
references.citation: J Invest Dermatol. 2008 Sep;128(9):2190-7
references.pmid: 18385757
references.citation: Blood. 1990 Feb 1;75(3):577-82
references.pmid: 2297568
references.citation: J Biol Chem. 1997 May 30;272(22):14029-32
references.pmid: 9162022
references.citation: Nature. 2008 Jun 5;453(7196):807-11
references.pmid: 18432192
references.citation: Nat Rev Mol Cell Biol. 2004 May;5(5):343-54
references.pmid: 15122348
references.citation: Lancet. 2003 Oct 18;362(9392):1255-60
references.pmid: 14575968
references.citation: Kidney Int. 1993 Nov;44(5):1149-62
references.pmid: 8264149
references.citation: Proc Natl Acad Sci U S A. 2011 Mar 22;108(12):4986-90
references.pmid: 21383158
references.citation: Cardiovasc Hematol Agents Med Chem. 2006 Jul;4(3):189-97
references.pmid: 16842205
references.citation: Blood. 2010 Oct 21;116(16):3039-48
references.pmid: 20628150
references.citation: Science. 2001 Apr 20;292(5516):464-8
references.pmid: 11292862
references.citation: J Clin Invest. 2007 Apr;117(4):1068-77
references.pmid: 17404621
references.citation: J Leukoc Biol. 2006 Feb;79(2):330-8
references.pmid: 16275888
references.citation: Cell. 2008 Apr 18;133(2):223-34
references.pmid: 18423195
references.citation: Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8725-9
references.pmid: 1924331
references.citation: Am J Physiol Cell Physiol. 2003 Feb;284(2):C439-46
references.pmid: 12388069
references.citation: Cell. 1996 Nov 1;87(3):427-36
references.pmid: 8898196
references.citation: Intern Med. 2004 Aug;43(8):649-59
references.pmid: 15468961
references.citation: J Clin Oncol. 2007 Mar 20;25(9):1027-32
references.pmid: 17312332
references.citation: Mol Cell. 2007 Apr 13;26(1):63-74
references.pmid: 17434127
references.citation: J Immunol Methods. 1994 Sep 14;174(1-2):83-93
references.pmid: 8083541
references.citation: J Biol Chem. 2003 May 30;278(22):19575-8
references.pmid: 12639949
references.citation: J Clin Oncol. 2005 Sep 1;23(25):5960-72
references.pmid: 16087945
references.citation: Semin Dial. 2006 Jan-Feb;19(1):1-4
references.pmid: 16423172
references.citation: Science. 2001 Apr 20;292(5516):468-72
references.pmid: 11292861
references.citation: Br J Cancer. 2006 Aug 7;95(3):272-81
references.pmid: 16832418
references.citation: Annu Rev Immunol. 2010;28:389-411
references.pmid: 20307212
references.citation: Am J Physiol Regul Integr Comp Physiol. 2004 Jun;286(6):R977-88
references.pmid: 15142852
references.citation: Curr Opin Oncol. 2010 Jul;22(4):307-11
references.pmid: 20498598
references.citation: J Clin Invest. 1988 Feb;81(2):620-3
references.pmid: 3339134
references.citation: Cell Signal. 2010 Mar;22(3):349-56
references.pmid: 19861159