title: Escherichia coli Nissle 1917 distinctively modulates T-cell cycling and expansion via toll-like receptor 2 signaling.
abstract: Although the probiotic Escherichia coli strain Nissle 1917 has been proven to be efficacious for the treatment of inflammatory bowel diseases, the underlying mechanisms of action still remain elusive. The aim of the present study was to analyze the effects of E. coli Nissle 1917 on cell cycling and apoptosis of peripheral blood and lamina propria T cells (PBT and LPT, respectively). Anti-CD3-stimulated PBT and LPT were treated with E. coli Nissle 1917-conditioned medium (E. coli Nissle 1917-CM) or heat-inactivated E. coli Nissle 1917. Cyclin B1, DNA content, and caspase 3 expression were measured by flow cytometry to assess cell cycle kinetics and apoptosis. Protein levels of several cell cycle and apoptosis modulators were determined by immunoblotting, and cytokine profiles were determined by cytometric bead array. E. coli Nissle 1917-CM inhibits cell cycling and expansion of peripheral blood but not mucosal T cells. Bacterial lipoproteins mimicked the effect of E. coli Nissle 1917-CM; in contrast, heat-inactivated E. coli Nissle 1917, lipopolysaccharide, or CpG DNA did not alter PBT cell cycling. E. coli Nissle 1917-CM decreased cyclin D2, B1, and retinoblastoma protein expression, contributing to the reduction of T-cell proliferation. E. coli Nissle 1917 significantly inhibited the expression of interleukin-2 (IL-2), tumor necrosis factor alpha, and gamma interferon but increased IL-10 production in PBT. Using Toll-like receptor 2 (TLR-2) knockout mice, we further demonstrate that the inhibition of PBT proliferation by E. coli Nissle 1917-CM is TLR-2 dependent. The differential reaction of circulating and tissue-bound T cells towards E. coli Nissle 1917 may explain the beneficial effect of E. coli Nissle 1917 in intestinal inflammation. E. coli Nissle 1917 may downregulate the expansion of newly recruited T cells into the mucosa and limit intestinal inflammation, while already activated tissue-bound T cells may eliminate deleterious antigens in order to maintain immunological homeostasis.
authors.affiliation: Department of Hepatology and Gastroenterology, Campus Virchow Clinic, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany. andreas.sturm@charite.de
authors.forename: Andreas
authors.initials: A
authors.lastname: Sturm
authors.forename: Klaus
authors.initials: K
authors.lastname: Rilling
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Baumgart
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Gargas
authors.forename: Tay
authors.initials: T
authors.lastname: Abou-Ghazalé
authors.forename: Bärbel
authors.initials: B
authors.lastname: Raupach
authors.forename: Jana
authors.initials: J
authors.lastname: Eckert
authors.forename: Ralf R
authors.initials: RR
authors.lastname: Schumann
authors.forename: Corinne
authors.initials: C
authors.lastname: Enders
authors.forename: Ulrich
authors.initials: U
authors.lastname: Sonnenborn
authors.forename: Bertram
authors.initials: B
authors.lastname: Wiedenmann
authors.forename: Axel U
authors.initials: AU
authors.lastname: Dignass
mesh_terms: D017209:Apoptosis; D002453:Cell Cycle; D002455:Cell Division; D004926:Escherichia coli / Q000276:immunology*; D005786:Gene Expression Regulation; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D019936:Probiotics; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors
chemical_list: D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors
references.citation: Gastroenterology. 1998 Dec;115(6):1405-13
references.pmid: 9834268
references.citation: Cell. 1999 Jan 22;96(2):245-54
references.pmid: 9988219
references.citation: Annu Rev Immunol. 1999;17:221-53
references.pmid: 10358758
references.citation: Gastroenterol Clin North Am. 1999 Jun;28(2):323-51
references.pmid: 10372271
references.citation: FEMS Immunol Med Microbiol. 1999 Nov;26(2):131-5
references.pmid: 10536299
references.citation: Immunity. 1999 Oct;11(4):443-51
references.pmid: 10549626
references.citation: Nat Cell Biol. 1999 Sep;1(5):E131-8
references.pmid: 10559956
references.citation: Science. 2000 Aug 25;289(5483):1311-2
references.pmid: 10979858
references.citation: Aliment Pharmacol Ther. 1997 Dec;11 Suppl 3:81-5; discussion 85-8
references.pmid: 9467982
references.citation: Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):5045-50
references.pmid: 9560225
references.citation: Cytometry. 1998 Jun 1;32(2):71-7
references.pmid: 9627219
references.citation: Genes Dev. 1999 Jun 15;13(12):1501-12
references.pmid: 10385618
references.citation: Science. 1999 Jul 30;285(5428):736-9
references.pmid: 10426996
references.citation: J Immunol. 1999 Aug 15;163(4):1742-5
references.pmid: 10438903
references.citation: Lancet. 1999 Aug 21;354(9179):635-9
references.pmid: 10466665
references.citation: Gastroenterology. 1999 Oct;117(4):761-9
references.pmid: 10500056
references.citation: Am J Gastroenterol. 2000 Jan;95(1 Suppl):S19-21
references.pmid: 10634224
references.citation: Immunol Cell Biol. 2000 Feb;78(1):55-66
references.pmid: 10651930
references.citation: J Immunol. 2000 Jul 15;165(2):931-40
references.pmid: 10878368
references.citation: Gastroenterology. 2000 Aug;119(2):305-9
references.pmid: 10930365
references.citation: Cytometry. 2000 Sep 1;41(1):1-8
references.pmid: 10942890
references.citation: Immunol Today. 2000 Nov;21(11):551-5
references.pmid: 11094258
references.citation: N Engl J Med. 2001 Mar 1;344(9):655-64
references.pmid: 11228281
references.citation: Gastroenterology. 2001 Feb;120(3):622-35
references.pmid: 11179240
references.citation: Gut. 2001 Mar;48(3):320-5
references.pmid: 11171820
references.citation: Gut. 2001 May;48(5):609
references.pmid: 11302956
references.citation: Nature. 2001 Jun 14;411(6839):820-4
references.pmid: 11459064
references.citation: Infect Immun. 2001 Sep;69(9):5529-37
references.pmid: 11500426
references.citation: N Engl J Med. 2001 Oct 11;345(15):1098-104
references.pmid: 11596589
references.citation: Gastroenterology. 2001 Nov;121(5):1145-57
references.pmid: 11677207
references.citation: Am J Gastroenterol. 2001 Nov;96(11):3218-9
references.pmid: 11721788
references.citation: Scand J Gastroenterol Suppl. 2001;(234):29-40
references.pmid: 11768558
references.citation: Gastroenterology. 2002 Jan;122(1):44-54
references.pmid: 11781279
references.citation: Gut. 2002 Feb;50(2):206-11
references.pmid: 11788561
references.citation: Annu Rev Immunol. 2002;20:709-60
references.pmid: 11861616
references.citation: J Rheumatol. 2002 Apr;29(4):647-9
references.pmid: 11950000
references.citation: Mol Immunol. 2002 May;38(14):1051-61
references.pmid: 11955597
references.citation: J Immunol. 2002 May 1;168(9):4531-7
references.pmid: 11970999
references.citation: Gastroenterology. 2002 May;122(5):1334-45
references.pmid: 11984520
references.citation: BioDrugs. 2002;16(2):111-48
references.pmid: 11985485
references.citation: J Clin Invest. 2002 Jun;109(11):1481-92
references.pmid: 12045262
references.citation: Aliment Pharmacol Ther. 2002 Aug;16(8):1383-93
references.pmid: 12182739
references.citation: Immunol Rev. 2002 Jul;185:86-102
references.pmid: 12190925
references.citation: Curr Opin Cell Biol. 2002 Dec;14(6):684-91
references.pmid: 12473340
references.citation: J Biol Chem. 2002 Dec 27;277(52):50959-65
references.pmid: 12393915
references.citation: J Immunol. 2003 Jan 1;170(1):194-200
references.pmid: 12496400
references.citation: Crit Rev Immunol. 2002;22(3):217-50
references.pmid: 12498384
references.citation: Nat Rev Cancer. 2003 Feb;3(2):130-8
references.pmid: 12563312
references.citation: Science. 2003 Feb 14;299(5609):1033-6
references.pmid: 12532024
references.citation: J Exp Med. 2003 Feb 17;197(4):403-11
references.pmid: 12591899
references.citation: Annu Rev Immunol. 2003;21:305-34
references.pmid: 12471050
references.citation: Scand J Gastroenterol. 2003 Feb;38(2):172-9
references.pmid: 12678334
references.citation: Gastroenterology. 2003 May;124(5):1202-9
references.pmid: 12730861
references.citation: FEBS Lett. 2003 Jun 5;544(1-3):4-10
references.pmid: 12782281
references.citation: Inflamm Bowel Dis. 2003 May;9(3):210-1
references.pmid: 12797349
references.citation: Clin Exp Immunol. 2003 Oct;134(1):127-37
references.pmid: 12974765
references.citation: Gut. 2004 Jan;53(1):108-14
references.pmid: 14684584
references.citation: Gastroenterology. 2004 Feb;126(2):520-8
references.pmid: 14762789
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):3029-34
references.pmid: 14981245
references.citation: Clin Diagn Lab Immunol. 2004 Mar;11(2):372-8
references.pmid: 15013990
references.citation: J Immunol. 2004 Apr 1;172(7):4463-9
references.pmid: 15034062
references.citation: Cytometry. 1985 Nov;6(6):620-6
references.pmid: 4064842
references.citation: J Immunol. 1992 Oct 15;149(8):2816-22
references.pmid: 1383328
references.citation: Lancet. 1994 Oct 22;344(8930):1105-10
references.pmid: 7934491
references.citation: Cell. 1994 Nov 18;79(4):551-5
references.pmid: 7954821
references.citation: Cell. 1995 May 5;81(3):323-30
references.pmid: 7736585
references.citation: J Cell Biochem. 1995 Jun;58(2):175-80
references.pmid: 7673325
references.citation: Gastroenterology. 1995 Oct;109(4):1029-38
references.pmid: 7557067
references.citation: Immunol Today. 1995 Jul;16(7):322-4
references.pmid: 7576064
references.citation: Clin Exp Immunol. 1995 Dec;102(3):448-55
references.pmid: 8536356
references.citation: Eur J Immunol. 1996 Apr;26(4):934-8
references.pmid: 8625991
references.citation: Semin Immunol. 1997 Feb;9(1):1-5
references.pmid: 9106302
references.citation: Immunol Rev. 1997 Apr;156:145-66
references.pmid: 9176706
references.citation: N Engl J Med. 1997 Oct 9;337(15):1029-35
references.pmid: 9321530
references.citation: Aliment Pharmacol Ther. 1997 Oct;11(5):853-8
references.pmid: 9354192
references.citation: Digestion. 1997;58(5):469-75
references.pmid: 9383639
references.citation: Gastroenterology. 1998 Jul;115(1):182-205
references.pmid: 9649475