title: Helicobacter pylori induces ERK-dependent formation of a phospho-c-Fos c-Jun activator protein-1 complex that causes apoptosis in macrophages.
abstract: Macrophages are essential components of innate immunity, and apoptosis of these cells impairs mucosal defense to microbes. Helicobacter pylori is a gastric pathogen that infects half of the world population and causes peptic ulcer disease and gastric cancer. The host inflammatory response fails to eradicate the organism. We have reported that H. pylori induces apoptosis of macrophages by generation of polyamines from ornithine decarboxylase (ODC), which is dependent on c-Myc as a transcriptional enhancer. We have now demonstrated that expression of c-Myc requires phosphorylation and nuclear translocation of ERK, which results in phosphorylation of c-Fos and formation of a specific activator protein (AP)-1 complex. Electromobility shift assay and immunoprecipitation revealed a previously unrecognized complex of phospho-c-Fos (pc-Fos) and c-Jun in the nucleus. Fluorescence resonance energy transfer demonstrated the interaction of pc-Fos and c-Jun. The capacity of this AP-1 complex to bind to putative AP-1 sequences was demonstrated by oligonucleotide pulldown and fluorescence polarization. Binding of the pc-Fos.c-Jun complex to the c-Myc promoter was demonstrated by chromatin immunoprecipitation. A dominant-negative c-Fos inhibited H. pylori-induced expression of c-Myc and ODC and apoptosis. H. pylori infection of mice induced a rapid infiltration of macrophages into the stomach. Concomitant apoptosis depleted these cells, and this was associated with formation of a pc-Fos.c-Jun complex. Treatment of mice with an inhibitor of ERK phosphorylation attenuated phosphorylation of c-Fos, expression of ODC, and apoptosis in gastric macrophages. A unique AP-1 complex in gastric macrophages contributes to the immune escape of H. pylori.
authors.affiliation: Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Asim
authors.forename: Rupesh
authors.initials: R
authors.lastname: Chaturvedi
authors.forename: Svea
authors.initials: S
authors.lastname: Hoge
authors.forename: Nuruddeen D
authors.initials: ND
authors.lastname: Lewis
authors.forename: Kshipra
authors.initials: K
authors.lastname: Singh
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Barry
authors.forename: Holly S
authors.initials: HS
authors.lastname: Algood
authors.forename: Thibaut
authors.initials: T
authors.lastname: de Sablet
authors.forename: Alain P
authors.initials: AP
authors.lastname: Gobert
authors.forename: Keith T
authors.initials: KT
authors.lastname: Wilson
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D031541:Fluorescence Resonance Energy Transfer; D016481:Helicobacter Infections / Q000235:genetics / Q000378:metabolism / Q000382:microbiology; D016480:Helicobacter pylori / Q000502:physiology*; D054884:Host-Pathogen Interactions; D007093:Imidazoles / Q000494:pharmacology; D015151:Immunoblotting; D046911:Macromolecular Substances / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009955:Ornithine Decarboxylase / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000873:Anthracenes; D005419:Flavonoids; D007093:Imidazoles; D046911:Macromolecular Substances; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D011725:Pyridines; D018808:Transcription Factor AP-1; C432165:pyrazolanthrone; D048049:Extracellular Signal-Regulated MAP Kinases; D009955:Ornithine Decarboxylase; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
references.citation: PLoS Pathog. 2006 Oct;2(10):e110
references.pmid: 17121461
references.citation: Annu Rev Microbiol. 1999;53:155-87
references.pmid: 10547689
references.citation: EMBO J. 1997 Apr 1;16(7):1695-709
references.pmid: 9130714
references.citation: J Biol Chem. 2003 Dec 12;278(50):50024-30
references.pmid: 14523011
references.citation: Mol Cell Biol. 1992 Aug;12(8):3507-13
references.pmid: 1630458
references.citation: Nature. 1994 Sep 8;371(6493):171-5
references.pmid: 8072547
references.citation: FEMS Immunol Med Microbiol. 2008 Aug;53(3):385-94
references.pmid: 18625013
references.citation: Nat Cell Biol. 2002 Aug;4(8):556-64
references.pmid: 12134156
references.citation: Mol Biol Cell. 2005 Oct;16(10):4954-66
references.pmid: 16030249
references.citation: Cell. 1992 Apr 3;69(1):119-28
references.pmid: 1555236
references.citation: Gastroenterology. 1996 Dec;111(6):1524-33
references.pmid: 8942731
references.citation: J Biol Chem. 2004 Sep 17;279(38):40161-73
references.pmid: 15247269
references.citation: Am J Physiol Gastrointest Liver Physiol. 2006 Jul;291(1):G73-81
references.pmid: 16469828
references.citation: EMBO J. 1998 Aug 3;17(15):4404-13
references.pmid: 9687508
references.citation: Science. 2001 Jun 29;292(5526):2439-40
references.pmid: 11431552
references.citation: Gastroenterology. 2009 Jan;136(1):247-56
references.pmid: 18948106
references.citation: Nat Rev Cancer. 2002 Jan;2(1):28-37
references.pmid: 11902583
references.citation: Anal Biochem. 2002 Sep 1;308(1):18-25
references.pmid: 12234459
references.citation: Cancer Res. 2004 Dec 1;64(23):8521-5
references.pmid: 15574757
references.citation: Proc Natl Acad Sci U S A. 2005 Apr 5;102(14):5186-91
references.pmid: 15795379
references.citation: J Biol Chem. 2000 Nov 17;275(46):36295-302
references.pmid: 10942775
references.citation: J Biol Chem. 2005 Jun 10;280(23):22492-6
references.pmid: 15843384
references.citation: Gastroenterology. 2007 Mar;132(3):1024-38
references.pmid: 17383425
references.citation: Mol Cell Biol. 2003 Oct;23(19):7030-43
references.pmid: 12972619
references.citation: FEMS Immunol Med Microbiol. 2007 Dec;51(3):577-86
references.pmid: 17919297
references.citation: Nature. 2001 Nov 15;414(6861):265-6
references.pmid: 11713514
references.citation: Cancer Res. 2006 Jul 1;66(13):6834-42
references.pmid: 16818661
references.citation: J Biol Chem. 1999 Oct 29;274(44):31655-62
references.pmid: 10531374
references.citation: Biochem J. 2004 Aug 1;381(Pt 3):635-44
references.pmid: 15109307
references.citation: Oncogene. 2007 May 14;26(22):3291-310
references.pmid: 17496923
references.citation: FEBS J. 2010 Jan;277(1):30-8
references.pmid: 19843172
references.citation: Gut. 2005 Nov;54(11):1536-40
references.pmid: 15985559
references.citation: Oncogene. 2001 Jan 11;20(2):147-55
references.pmid: 11313944
references.citation: Infect Immun. 2007 Sep;75(9):4305-15
references.pmid: 17562760
references.citation: Gastroenterology. 2007 Jul;133(1):288-308
references.pmid: 17631150
references.citation: Oncogene. 1996 Apr 4;12(7):1493-502
references.pmid: 8622865
references.citation: J Immunol. 2008 Apr 1;180(7):5017-27
references.pmid: 18354227
references.citation: Biochim Biophys Acta. 1991 Dec 10;1072(2-3):129-57
references.pmid: 1751545
references.citation: J Immunol. 2010 Mar 1;184(5):2572-82
references.pmid: 20097867
references.citation: J Biol Chem. 1992 Sep 15;267(26):18278-83
references.pmid: 1526968
references.citation: Anal Biochem. 2005 May 15;340(2):259-71
references.pmid: 15840499
references.citation: Biochem J. 2002 Nov 15;368(Pt 1):121-9
references.pmid: 12150710
references.citation: J Cell Biol. 2003 Mar 3;160(5):629-33
references.pmid: 12615908
references.citation: Mol Cell Biol. 1992 Mar;12(3):915-27
references.pmid: 1545823
references.citation: Mol Cell Biol. 1996 Jan;16(1):211-8
references.pmid: 8524298
references.citation: J Immunol. 2008 Jan 15;180(2):1207-16
references.pmid: 18178861
references.citation: Cell Growth Differ. 1991 Oct;2(10):475-82
references.pmid: 1751404
references.citation: Mol Cell Biol. 2000 Jul;20(14):5276-84
references.pmid: 10866684
references.citation: FEBS J. 2010 Jan;277(1):2-21
references.pmid: 19843174
references.citation: Proc Natl Acad Sci U S A. 1986 Jul;83(13):4794-8
references.pmid: 3523478
references.citation: Neuron. 1995 May;14(5):927-39
references.pmid: 7748560
references.citation: Proc Natl Acad Sci U S A. 1999 Oct 26;96(22):12866-9
references.pmid: 10536014
references.citation: Mol Cell. 2003 Feb;11(2):405-13
references.pmid: 12620228
references.citation: Nat Cell Biol. 2002 May;4(5):E131-6
references.pmid: 11988758
references.citation: Curr Opin Cell Biol. 1997 Apr;9(2):240-6
references.pmid: 9069263
references.citation: Gastroenterology. 2007 Mar;132(3):1009-23
references.pmid: 17383424
references.citation: J Biol Chem. 1997 Jul 25;272(30):19008-16
references.pmid: 9228083
references.citation: J Biol Chem. 2008 Jun 13;283(24):16752-61
references.pmid: 18417477
references.citation: J Immunol. 1999 Nov 15;163(10):5552-9
references.pmid: 10553083
references.citation: J Immunol. 2002 May 1;168(9):4692-700
references.pmid: 11971019
references.citation: J Biol Chem. 2001 Nov 9;276(45):41755-60
references.pmid: 11546808
references.citation: J Biol Chem. 1997 Jul 25;272(30):18586-94
references.pmid: 9228025