Epithelial cell expression of BCL-2 family proteins predicts mechanisms that regulate Helicobacter pylori-induced pathology in the mouse stomach.
Corpus-predominant infection with Helicobacter pylori (HP) results in the activation of programmed cell death pathways in surface, parietal, and chief cells. At present, mechanisms that regulate these pathways to result in HP-associated pathology are not fully understood. Because it is not known which survival and death pathways are present in gastric epithelial cells, we used an antibody panel to evaluate the expression of BCL-2 family prosurvival proteins or multi-Bcl-2 homology (BH)-domains (group 1) or BH3-only (group-2) proapoptotic proteins in the stomachs of uninfected or HP-infected C57BL/6 mice. This strategy identified BCL-2, BAK, and BAD as the major prosurvival and proapoptotic proteins, in surface cells and BAD as the only BCL-2 family protein expressed in parietal cells. Chief cells express altogether different effectors, including BCL-X(L)/BCL-2, for survival but have no constitutively expressed proapoptotic proteins. In model chief cells, however, the group 1 proapoptotic protein BCL-X(S) was expressed after exposure to proinflammatory cytokines concomitant with reduced viability, demonstrating that chief cells can transcriptionally regulate the induction of proapoptotic proteins to execute apoptosis. During HP infection, no additional BCL-2 family proteins were expressed in epithelial cells, whereas those present either remained unchanged or were reduced as cell deletion occurred over time. Additional studies demonstrated that the posttranslational regulation of BAD in surface and parietal cells was negatively affected by HP infection, a result that may be directly related to an increase in apoptosis during infection. Thus, gastric epithelial cells express cell-specific prosurvival and proapoptotic pathways. From the results presented here, mechanisms that regulate HP-related changes in the survival and death profile of gastric epithelial cells can be predicted and then tested, with the ultimate goal of elucidating important therapeutic targets to inhibit the progression of HP-related pathology in the stomach.
Hagen
Susan J
SJ
Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. shagen@bidmc.harvard.edu
Yang
David X
DX
Tashima
Kimihito
K
Taylor
Nancy S
NS
Fox
James G
JG
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D019872:Chief Cells, Gastric / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D016481:Helicobacter Infections / Q000503:physiopathology*; D016480:Helicobacter pylori; D051379:Mice; D010295:Parietal Cells, Gastric / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D013272:Stomach Diseases / Q000382:microbiology / Q000503:physiopathology*; D051025:bcl-Associated Death Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
C494820:Bad protein, mouse; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein
Methods Enzymol. 1990;191:640-61
1963655
Cancer Res. 1999 Oct 1;59(19):4823-8
10519391
J Clin Invest. 1998 Mar 15;101(6):1243-53
9502765
Annu Rev Physiol. 1994;56:445-61
8010747
Gastroenterology. 2003 Jun;124(7):1879-90
12806621
Am J Physiol. 1994 Dec;267(6 Pt 1):G1012-20
7810647
Science. 1997 Oct 24;278(5338):687-9
9381178
Acta Gastroenterol Belg. 2006 Apr-Jun;69(2):191-6
16929614
J Cell Sci. 2002 Apr 15;115(Pt 8):1567-74
11950875
J Gastroenterol Hepatol. 2007 Mar;22(3):355-62
17295767
Prog Neurobiol. 2007 Feb;81(3):179-96
17267093
J Biol Chem. 1997 May 2;272(18):11791-8
9115235
Cancer Cell. 2002 Sep;2(3):183-92
12242151
Proc Natl Acad Sci U S A. 1997 Jun 24;94(13):6939-42
9192670
Mol Cell. 1999 Apr;3(4):413-22
10230394
Am J Pathol. 1994 Dec;145(6):1323-36
7992838
Am J Physiol Gastrointest Liver Physiol. 2002 Oct;283(4):G986-95
12223359
Scand J Gastroenterol. 1999 Apr;34(4):375-83
10365897
Oncogene. 1999 Nov 18;18(48):6635-40
10597268
Cell. 1993 Aug 27;74(4):597-608
8358789
Microsc Res Tech. 2001 Jun 1;53(5):377-88
11376499
Anat Rec. 1993 Jun;236(2):297-313
8338234
Biochem Biophys Res Commun. 1998 Nov 9;252(1):92-6
9813151
J Biol Chem. 2003 May 16;278(20):18022-9
12637494
Neurochem Res. 2001 Jun;26(6):647-59
11519724
J Biol Chem. 2000 Aug 11;275(32):25046-51
10837473
J Biol Chem. 2002 Aug 2;277(31):27643-50
12011069
Cell. 1997 Oct 17;91(2):231-41
9346240
Science. 2007 Feb 9;315(5813):856-9
17289999
Biochim Biophys Acta. 1986 Aug 29;888(1):116-25
3741886
Mol Cell Neurosci. 2001 Jan;17(1):97-106
11161472
Am J Physiol Gastrointest Liver Physiol. 2002 Aug;283(2):G309-18
12121877
Cell. 1995 Jan 27;80(2):285-91
7834748
Biochem Pharmacol. 2003 May 15;65(10):1755-60
12754112
Gastroenterology. 1997 Apr;112(4):1386-97
9098027
Cell Death Differ. 2002 May;9(5):505-12
11973609
Biochem Biophys Res Commun. 1995 Oct 13;215(2):511-6
7487985
J Biol Chem. 2005 Sep 2;280(35):31091-100
15994315
Mol Cell Endocrinol. 2002 Mar 28;189(1-2):1-9
12039060
Biochem Biophys Res Commun. 2005 Jul 29;333(2):336-43
15922292
J Biol Chem. 2001 Jun 15;276(24):21062-9
11274164
Mol Cell. 2000 Dec;6(6):1389-99
11163212
Am J Physiol Gastrointest Liver Physiol. 2002 Dec;283(6):G1264-75
12388179
Anat Rec. 1993 Jun;236(2):314-32
8338235
Am J Physiol. 1997 Jan;272(1 Pt 1):G161-71
9038890
Gastroenterology. 1996 Jan;110(1):155-66
8536852
Gastroenterology. 1998 Apr;114(4):675-89
9516388
J Membr Biol. 1997 Sep 15;159(2):99-111
9307437
Histol Histopathol. 2001 Apr;16(2):595-601
11332715
Gastroenterology. 1994 Jan;106(1):73-84
8276211
J Biol Chem. 2001 Dec 7;276(49):46436-44
11564730
Cell. 2004 Jan 23;116(2):205-19
14744432
Am J Physiol. 1996 Oct;271(4 Pt 1):G640-9
8897883
Am J Physiol. 1993 Feb;264(2 Pt 1):G390-6
8447422
J Biol Chem. 2004 Mar 12;279(11):9831-9
14679196
Cell Signal. 2006 Apr;18(4):531-40
15972258
Am J Physiol. 1994 Apr;266(4 Pt 1):G745-58
8179010
Lab Invest. 2006 Oct;86(10):1037-51
16894354
Science. 2007 Feb 9;315(5813):776-7
17289967
Annu Rev Immunol. 2003;21:71-105
12414721
Am J Physiol. 1997 Jan;272(1 Pt 1):C48-58
9038810
J Biol Chem. 1996 Mar 15;271(11):6306-12
8626425
Nat Immunol. 2003 May;4(5):410-5
12719730