title: Immunoregulatory effect of bifidobacteria strains in porcine intestinal epithelial cells through modulation of ubiquitin-editing enzyme A20 expression.
abstract: BACKGROUND
  We previously showed that evaluation of anti-inflammatory activities of lactic acid bacteria in porcine intestinal epithelial (PIE) cells is useful for selecting potentially immunobiotic strains.
  
  
  OBJECTIVE
  The aims of the present study were: i) to select potentially immunomodulatory bifidobacteria that beneficially modulate the Toll-like receptor (TLR)-4-triggered inflammatory response in PIE cells and; ii) to gain insight into the molecular mechanisms involved in the anti-inflammatory effect of immunobiotics by evaluating the role of TLR2 and TLR negative regulators in the modulation of proinflammatory cytokine production and activation of mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) pathways in PIE cells.
  
  
  RESULTS
  Bifidobacteria longum BB536 and B. breve M-16V strains significantly downregulated levels of interleukin (IL)-8, monocyte chemotactic protein (MCP)-1 and IL-6 in PIE cells challenged with heat-killed enterotoxigenic Escherichia coli. Moreover, BB536 and M-16V strains attenuated the proinflammatory response by modulating the NF-κB and MAPK pathways. In addition, our findings provide evidence for a key role for the ubiquitin-editing enzyme A20 in the anti-inflammatory effect of immunobiotic bifidobacteria in PIE cells.
  
  
  CONCLUSIONS
  We show new data regarding the mechanism involved in the anti-inflammatory effect of immunobiotics. Several strains with immunoregulatory capabilities used a common mechanism to induce tolerance in PIE cells. Immunoregulatory strains interacted with TLR2, upregulated the expression of A20 in PIE cells, and beneficially modulated the subsequent TLR4 activation by reducing the activation of MAPK and NF-κB pathways and the production of proinflammatory cytokines. We also show that the combination of TLR2 activation and A20 induction can be used as biomarkers to screen and select potential immunoregulatory bifidobacteria strains.
authors.affiliation: Food and Feed Immunology Group, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan.
authors.forename: Yohsuke
authors.initials: Y
authors.lastname: Tomosada
authors.forename: Julio
authors.initials: J
authors.lastname: Villena
authors.forename: Kozue
authors.initials: K
authors.lastname: Murata
authors.forename: Eriko
authors.initials: E
authors.lastname: Chiba
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Shimazu
authors.forename: Hisashi
authors.initials: H
authors.lastname: Aso
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Iwabuchi
authors.forename: Jin-zhong
authors.initials: JZ
authors.lastname: Xiao
authors.forename: Tadao
authors.initials: T
authors.lastname: Saito
authors.forename: Haruki
authors.initials: H
authors.lastname: Kitazawa
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001644:Bifidobacterium / Q000737:chemistry* / Q000276:immunology; D001681:Biological Assay; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000276:immunology; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology*; D005786:Gene Expression Regulation; D056747:Immunomodulation; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D016209:Interleukin-8 / Q000235:genetics / Q000276:immunology; D007422:Intestines / Q000166:cytology / Q000276:immunology; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D019936:Probiotics / Q000494:pharmacology*; D015398:Signal Transduction; D013552:Swine; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology
chemical_list: D000893:Anti-Inflammatory Agents; D018932:Chemokine CCL2; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D020928:Mitogen-Activated Protein Kinases
references.citation: Nat Immunol. 2004 Oct;5(10):1052-60
references.pmid: 15334086
references.citation: J Allergy Clin Immunol. 2006 Mar;117(3):696-702
references.pmid: 16522473
references.citation: Nat Rev Immunol. 2010 Oct;10(10):735-44
references.pmid: 20865020
references.citation: Infect Immun. 2012 Jan;80(1):276-88
references.pmid: 22083706
references.citation: Gut. 2004 Nov;53(11):1602-9
references.pmid: 15479680
references.citation: Genes Dev. 2008 Aug 1;22(15):2093-101
references.pmid: 18676814
references.citation: FEBS Lett. 2004 Oct 8;576(1-2):86-90
references.pmid: 15474016
references.citation: Science. 2000 Sep 29;289(5488):2350-4
references.pmid: 11009421
references.citation: J Exp Med. 2008 Feb 18;205(2):451-64
references.pmid: 18268035
references.citation: Int J Med Microbiol. 2010 Jan;300(1):11-8
references.pmid: 19781991
references.citation: Immunology. 2008 Aug;124(4):489-502
references.pmid: 18217947
references.citation: Nat Rev Microbiol. 2010 Mar;8(3):171-84
references.pmid: 20157338
references.citation: Am J Physiol Gastrointest Liver Physiol. 2004 Apr;286(4):G613-26
references.pmid: 15010363
references.citation: Int J Food Microbiol. 2010 Mar 31;138(1-2):157-65
references.pmid: 20071048
references.citation: Immunity. 2007 Apr;26(4):461-75
references.pmid: 17398123
references.citation: FEMS Immunol Med Microbiol. 2011 Oct;63(1):129-39
references.pmid: 21711398
references.citation: Clin Vaccine Immunol. 2012 Jul;19(7):1038-53
references.pmid: 22573738
references.citation: Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6721-5
references.pmid: 8692885
references.citation: Nat Immunol. 2004 Jan;5(1):104-12
references.pmid: 14691478
references.citation: J Exp Med. 2010 Jul 5;207(7):1513-23
references.pmid: 20530205
references.citation: FEMS Immunol Med Microbiol. 2012 Dec;66(3):353-62
references.pmid: 22882710
references.citation: J Biol Chem. 2007 Feb 9;282(6):4102-12
references.pmid: 17135271
references.citation: J Mol Biol. 2008 Feb 15;376(2):526-40
references.pmid: 18164316
references.citation: Vet Res. 2011 Nov 03;42:111
references.pmid: 22046952
references.citation: Br J Nutr. 2012 Aug;108(3):459-70
references.pmid: 22054064
references.citation: Biochim Biophys Acta. 2008 Feb;1780(2):134-44
references.pmid: 18082146
references.citation: Proc Natl Acad Sci U S A. 2011 Mar 15;108 Suppl 1:4607-14
references.pmid: 20826446
references.citation: Am J Physiol Gastrointest Liver Physiol. 2007 Jun;292(6):G1469-73
references.pmid: 17554134
references.citation: Nat Rev Microbiol. 2011 Nov 21;10(1):66-78
references.pmid: 22101918
references.citation: J Microbiol Immunol Infect. 2013 Dec;46(6):474-81
references.pmid: 22727542
references.citation: J Immunol. 2009 Jul 15;183(2):1384-92
references.pmid: 19570823
references.citation: Immunity. 2008 Mar;28(3):381-90
references.pmid: 18342009