title: Role of fatty-acid synthesis in dendritic cell generation and function.
abstract: Dendritic cells (DC) are professional APCs that regulate innate and adaptive immunity. The role of fatty-acid synthesis in DC development and function is uncertain. We found that blockade of fatty-acid synthesis markedly decreases dendropoiesis in the liver and in primary and secondary lymphoid organs in mice. Human DC development from PBMC precursors was also diminished by blockade of fatty-acid synthesis. This was associated with higher rates of apoptosis in precursor cells and increased expression of cleaved caspase-3 and BCL-xL and downregulation of cyclin B1. Further, blockade of fatty-acid synthesis decreased DC expression of MHC class II, ICAM-1, B7-1, and B7-2 but increased their production of selected proinflammatory cytokines including IL-12 and MCP-1. Accordingly, inhibition of fatty-acid synthesis enhanced DC capacity to activate allogeneic as well as Ag-restricted CD4(+) and CD8(+) T cells and induce CTL responses. Further, blockade of fatty-acid synthesis increased DC expression of Notch ligands and enhanced their ability to activate NK cell immune phenotype and IFN-γ production. Because endoplasmic reticulum (ER) stress can augment the immunogenic function of APC, we postulated that this may account for the higher DC immunogenicity. We found that inhibition of fatty-acid synthesis resulted in elevated expression of numerous markers of ER stress in humans and mice and was associated with increased MAPK and Akt signaling. Further, lowering ER stress by 4-phenylbutyrate mitigated the enhanced immune stimulation associated with fatty-acid synthesis blockade. Our findings elucidate the role of fatty-acid synthesis in DC development and function and have implications to the design of DC vaccines for immunotherapy.
authors.affiliation: Department of Surgery, S. Arthur Localio Laboratory, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Adeel
authors.initials: A
authors.lastname: Rehman
authors.forename: Keith C
authors.initials: KC
authors.lastname: Hemmert
authors.forename: Atsuo
authors.initials: A
authors.lastname: Ochi
authors.forename: Mohsin
authors.initials: M
authors.lastname: Jamal
authors.forename: Justin R
authors.initials: JR
authors.lastname: Henning
authors.forename: Rocky
authors.initials: R
authors.lastname: Barilla
authors.forename: Juan P
authors.initials: JP
authors.lastname: Quesada
authors.forename: Constantinos P
authors.initials: CP
authors.lastname: Zambirinis
authors.forename: Kerry
authors.initials: K
authors.lastname: Tang
authors.forename: Melvin
authors.initials: M
authors.lastname: Ego-Osuala
authors.forename: Raghavendra S
authors.initials: RS
authors.lastname: Rao
authors.forename: Stephanie
authors.initials: S
authors.lastname: Greco
authors.forename: Michael
authors.initials: M
authors.lastname: Deutsch
authors.forename: Suchithra
authors.initials: S
authors.lastname: Narayan
authors.forename: H Leon
authors.initials: HL
authors.lastname: Pachter
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Graffeo
authors.forename: Devrim
authors.initials: D
authors.lastname: Acehan
authors.forename: George
authors.initials: G
authors.lastname: Miller
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D018122:B7-1 Antigen / Q000276:immunology / Q000378:metabolism; D051940:B7-2 Antigen / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D053148:Caspase 3 / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology*; D018932:Chemokine CCL2 / Q000276:immunology / Q000378:metabolism; D056744:Cyclin B1 / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000276:immunology / Q000378:metabolism; D005227:Fatty Acids / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism; D005802:Genes, MHC Class II / Q000276:immunology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008099:Liver / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020929:Mitogen-Activated Protein Kinase Kinases / Q000276:immunology / Q000378:metabolism; D047495:PPAR gamma / Q000276:immunology / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D051020:bcl-X Protein / Q000276:immunology / Q000378:metabolism
chemical_list: D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018932:Chemokine CCL2; D056744:Cyclin B1; D005227:Fatty Acids; D047495:PPAR gamma; D051020:bcl-X Protein; D018799:Intercellular Adhesion Molecule-1; D018664:Interleukin-12; D007371:Interferon-gamma; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases; D053148:Caspase 3
references.citation: Cancer Res. 2003 Nov 1;63(21):7330-7
references.pmid: 14612531
references.citation: Proc Natl Acad Sci U S A. 2005 Feb 15;102(7):2561-6
references.pmid: 15699349
references.citation: J Am Soc Nephrol. 2010 Jan;21(1):73-81
references.pmid: 19875812
references.citation: J Biol Chem. 2012 Apr 6;287(15):11629-41
references.pmid: 22356914
references.citation: Oncogene. 2001 Jun 7;20(26):3354-62
references.pmid: 11423986
references.citation: Cell Death Dis. 2012 Apr 05;3:e292
references.pmid: 22476100
references.citation: Curr Opin Immunol. 2010 Feb;22(1):124-30
references.pmid: 20083398
references.citation: J Neurochem. 2004 Apr;89(1):232-9
references.pmid: 15030407
references.citation: Gastroenterology. 2011 Nov;141(5):1915-26.e1-14
references.pmid: 21801698
references.citation: Semin Immunol. 2011 Feb;23(1):21-7
references.pmid: 21277223
references.citation: BMC Immunol. 2009 Feb 16;10:10
references.pmid: 19220912
references.citation: FASEB J. 2003 Apr;17(6):728-30
references.pmid: 12594171
references.citation: Int J Biochem Cell Biol. 2012 Jul;44(7):1078-86
references.pmid: 22497927
references.citation: Cell Death Differ. 2002 Jul;9(7):750-7
references.pmid: 12058280
references.citation: Nat Med. 2006 Feb;12(2):207-13
references.pmid: 16444266
references.citation: J Biol Chem. 2005 Apr 8;280(14):14293-301
references.pmid: 15684433
references.citation: Immunotherapy. 2010 Mar;2(2):257-68
references.pmid: 20635932
references.citation: Cancer Res. 2007 Apr 1;67(7):2964-71
references.pmid: 17409402
references.citation: Nat Rev Mol Cell Biol. 2012 Jan 18;13(2):89-102
references.pmid: 22251901
references.citation: Immunity. 2010 Oct 29;33(4):464-78
references.pmid: 21029958
references.citation: Nat Med. 2010 Aug;16(8):880-6
references.pmid: 20622859
references.citation: Cancer Res. 2005 Oct 1;65(19):9073-9
references.pmid: 16204082
references.citation: Proc Natl Acad Sci U S A. 2008 May 13;105(19):7010-5
references.pmid: 18458347
references.citation: Eur J Cell Biol. 2012 Jan;91(1):53-8
references.pmid: 21439674
references.citation: J Lipid Res. 2009 Dec;50(12):2486-501
references.pmid: 19461119
references.citation: J Leukoc Biol. 2008 Oct;84(4):1172-82
references.pmid: 18632990
references.citation: J Biol Chem. 2004 Jan 30;279(5):3817-27
references.pmid: 14615481
references.citation: Cancer Res. 2007 Feb 1;67(3):1262-9
references.pmid: 17283163
references.citation: Cancer Res. 2002 Sep 15;62(18):5260-6
references.pmid: 12234994
references.citation: Cancer Res. 2000 Jan 15;60(2):213-8
references.pmid: 10667561
references.citation: Blood. 2001 Sep 1;98(5):1512-23
references.pmid: 11520802
references.citation: J Leukoc Biol. 2009 Apr;85(4):664-72
references.pmid: 19164128
references.citation: Cell Death Differ. 2006 Mar;13(3):374-84
references.pmid: 16397578
references.citation: Proc Natl Acad Sci U S A. 2010 Oct 12;107(41):17698-703
references.pmid: 20876114
references.citation: Biochem Biophys Res Commun. 2002 May 24;293(5):1431-7
references.pmid: 12054675
references.citation: J Clin Invest. 2009 Nov;119(11):3213-25
references.pmid: 19855130
references.citation: J Immunol. 2001 Jul 15;167(2):957-65
references.pmid: 11441104
references.citation: Am J Physiol Endocrinol Metab. 2004 Dec;287(6):E1171-7
references.pmid: 15315910
references.citation: Diabetes. 2008 Mar;57(3):737-45
references.pmid: 18065517
references.citation: PLoS One. 2010 Sep 15;5(9):e12772
references.pmid: 20856677
references.citation: Gastroenterology. 2012 Oct;143(4):1061-72
references.pmid: 22705178
references.citation: Nature. 2007 Sep 27;449(7161):419-26
references.pmid: 17898760
references.citation: Autophagy. 2010 Feb;6(2):239-47
references.pmid: 20104019
references.citation: Biochem Biophys Res Commun. 2009 Jul 31;385(3):302-6
references.pmid: 19450551
references.citation: Cell Adh Migr. 2010 Apr-Jun;4(2):235-40
references.pmid: 20234187
references.citation: Cancer Biol Ther. 2011 Jul 1;12(1):80-5
references.pmid: 21525791
references.citation: Blood. 2005 Dec 1;106(12):3888-94
references.pmid: 16105976
references.citation: Blood. 2006 May 15;107(10):3950-8
references.pmid: 16434485
references.citation: Proc Natl Acad Sci U S A. 2002 Jul 9;99(14):9498-502
references.pmid: 12060712