title: Inflammation anergy in human intestinal macrophages is due to Smad-induced IkappaBalpha expression and NF-kappaB inactivation.
abstract: Human intestinal macrophages contribute to tissue homeostasis in noninflamed mucosa through profound down-regulation of pro-inflammatory cytokine release. Here, we show that this down-regulation extends to Toll-like receptor (TLR)-induced cytokine release, as intestinal macrophages expressed TLR3-TLR9 but did not release cytokines in response to TLR-specific ligands. Likely contributing to this unique functional profile, intestinal macrophages expressed markedly down-regulated adapter proteins MyD88 and Toll interleukin receptor 1 domain-containing adapter-inducing interferon beta, which together mediate all TLR MyD88-dependent and -independent NF-kappaB signaling, did not phosphorylate NF-kappaB p65 or Smad-induced IkappaBalpha, and did not translocate NF-kappaB into the nucleus. Importantly, transforming growth factor-beta released from intestinal extracellular matrix (stroma) induced identical down-regulation in the NF-kappaB signaling and function of blood monocytes, the exclusive source of intestinal macrophages. Our findings implicate stromal transforming growth factor-beta-induced dysregulation of NF-kappaB proteins and Smad signaling in the differentiation of pro-inflammatory blood monocytes into noninflammatory intestinal macrophages.
authors.affiliation: Department of Medicine Gastroenterology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA. lesmy@uab.edu.
authors.forename: Lesley E
authors.initials: LE
authors.lastname: Smythies
authors.forename: Ruizhong
authors.initials: R
authors.lastname: Shen
authors.forename: Diane
authors.initials: D
authors.lastname: Bimczok
authors.forename: Lea
authors.initials: L
authors.lastname: Novak
authors.forename: Ronald H
authors.initials: RH
authors.lastname: Clements
authors.forename: Devin E
authors.initials: DE
authors.lastname: Eckhoff
authors.forename: Phillipe
authors.initials: P
authors.lastname: Bouchard
authors.forename: Michael D
authors.initials: MD
authors.lastname: George
authors.forename: William K
authors.initials: WK
authors.lastname: Hu
authors.forename: Satya
authors.initials: S
authors.lastname: Dandekar
authors.forename: Phillip D
authors.initials: PD
authors.lastname: Smith
mesh_terms: D016207:Cytokines / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism*; D007249:Inflammation; D007413:Intestinal Mucosa / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D000072000:NF-KappaB Inhibitor alpha
references.citation: Clin Exp Immunol. 1997 Oct;110(1):104-13
references.pmid: 9353156
references.citation: J Immunol. 2004 Sep 1;173(5):2913-7
references.pmid: 15322147
references.citation: J Virol. 2009 Apr;83(7):3258-67
references.pmid: 19153236
references.citation: Nat Immunol. 2006 Oct;7(10):1074-81
references.pmid: 16964262
references.citation: Oncogene. 2006 Oct 30;25(51):6831-43
references.pmid: 17072331
references.citation: J Clin Invest. 1991 Mar;87(3):894-900
references.pmid: 1847939
references.citation: Eur J Immunol. 2007 Aug;37(8):2300-8
references.pmid: 17634956
references.citation: Nat Immunol. 2006 Feb;7(2):148-55
references.pmid: 16415872
references.citation: J Immunol. 2005 Jan 1;174(1):517-24
references.pmid: 15611278
references.citation: J Biol Chem. 2005 Feb 18;280(7):5491-5
references.pmid: 15623538
references.citation: J Clin Invest. 2001 Aug;108(4):601-9
references.pmid: 11518734
references.citation: J Virol. 2008 Jan;82(1):538-45
references.pmid: 17959677
references.citation: J Infect Dis. 2000 Sep;182(3):785-91
references.pmid: 10950772
references.citation: Mucosal Immunol. 2011 Jan;4(1):31-42
references.pmid: 20962772
references.citation: Immunol Rev. 2005 Aug;206:149-59
references.pmid: 16048547
references.citation: Nat Immunol. 2007 Oct;8(10):1086-94
references.pmid: 17873879
references.citation: J Clin Invest. 2007 Oct;117(10):3097-106
references.pmid: 17853946
references.citation: Nat Rev Immunol. 2007 May;7(5):353-64
references.pmid: 17457343
references.citation: J Biol Chem. 2005 Jun 24;280(25):23496-501
references.pmid: 15849198
references.citation: J Leukoc Biol. 2006 Nov;80(5):1111-7
references.pmid: 17056764
references.citation: Nat Immunol. 2005 Jun;6(6):565-70
references.pmid: 15895089
references.citation: J Immunol Methods. 1997 Mar 10;202(1):1-11
references.pmid: 9075766
references.citation: Nucleic Acids Res. 2001 May 1;29(9):e45
references.pmid: 11328886
references.citation: J Biol Chem. 2006 Apr 14;281(15):10489-95
references.pmid: 16439361
references.citation: J Biol Chem. 1999 Aug 13;274(33):23242-8
references.pmid: 10438498
references.citation: J Immunol. 2001 Sep 1;167(5):2651-6
references.pmid: 11509607
references.citation: J Biol Chem. 1994 Apr 15;269(15):11425-34
references.pmid: 7512565
references.citation: Eur J Immunol. 2008 Jun;38(6):1533-47
references.pmid: 18461564
references.citation: J Clin Invest. 2005 Jan;115(1):66-75
references.pmid: 15630445
references.citation: J Biol Chem. 2004 Feb 6;279(6):3925-32
references.pmid: 14600158
references.citation: Nature. 2006 May 25;441(7092):431-6
references.pmid: 16724054
references.citation: Gastroenterology. 1999 May;116(5):1043-53
references.pmid: 10220496
references.citation: Nat Immunol. 2002 Jul;3(7):667-72
references.pmid: 12055629
references.citation: Semin Immunol. 2004 Feb;16(1):3-9
references.pmid: 14751757
references.citation: J Exp Med. 1999 Oct 4;190(7):995-1004
references.pmid: 10510089
references.citation: Infect Immun. 2000 May;68(5):2418-23
references.pmid: 10768925
references.citation: Gastroenterology. 2005 Nov;129(5):1420-9
references.pmid: 16285943
references.citation: J Leukoc Biol. 2006 Sep;80(3):492-9
references.pmid: 16793909
references.citation: Cell. 2008 Feb 8;132(3):344-62
references.pmid: 18267068