title: The critical role of toll-like receptor (TLR) 4 in alcoholic liver disease is independent of the common TLR adapter MyD88.
abstract: The Toll-like receptor 4 (TLR4) that recognizes endotoxin, a trigger of inflammation in alcoholic liver disease (ALD), activates two signaling pathways utilizing different adapter molecules: the common TLR adapter, myeloid differentiation factor 88 (MyD88), or Toll/interleukin immune-response-domain-containing adaptor inducing interferon (IFN)-beta. The MyD88 pathway induces proinflammatory cytokine activation, a critical mediator of ALD. Here we evaluated the role of MyD88 in alcohol-induced liver injury in wild-type, TLR2-deficient, TLR4-deficient, or MyD88-deficient (knockout [KO]) mice after administration of the Lieber-De-Carli diet (4.5% volume/volume ethanol) or an isocaloric liquid control diet for 5 weeks. Alcohol feeding resulted in a significant increase in serum alanine aminotransferase levels, liver steatosis and triglyceride levels suggesting liver damage in WT, TLR2-KO, and MyD88-KO but not in TLR4-KO mice. Expression of inflammatory mediators (tumor necrosis factor-alpha and interleukin-6) and TLR4 coreceptors (CD14 and MD2) was significantly higher in livers of alcohol-fed WT, TLR2-KO, or MyD88-KO, but not in TLR4-KO mice, compared to controls. Reactive oxygen radicals produced by cytochrome P450 and the nicotinamide adenine dinucleotide phosphate complexes contribute to alcoholic liver damage. Alcohol feeding-induced expression and activation of cytochrome P450 and the nicotinamide adenine dinucleotide phosphate complex were prevented by TLR4-deficiency but not by MyD88-deficiency. Liver expression of interferon regulatory factor 3 (IRF3), a MyD88-independent signaling molecule, was not affected by chronic alcohol treatment in whole livers of WT mice or in any of the KO mice. However, the induction of IRF7, an IRF3-inducible gene, was found in Kupffer cells of alcohol-fed WT mice. Alcohol feeding also induced nuclear factor-kappaB activation in a TLR4-dependent MyD88-independent manner.
  
  
  CONCLUSIONS
  While TLR4 deficiency was protective, MyD88 deficiency failed to prevent alcohol-induced liver damage and inflammation. These results suggest that the common TLR adapter, MyD88, is dispensable in TLR4-mediated liver injury in ALD.
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, University of Massachusetts, Worcester, MA 01605, USA.
authors.forename: Istvan
authors.initials: I
authors.lastname: Hritz
authors.forename: Pranoti
authors.initials: P
authors.lastname: Mandrekar
authors.forename: Arumugam
authors.initials: A
authors.lastname: Velayudham
authors.forename: Donna
authors.initials: D
authors.lastname: Catalano
authors.forename: Angela
authors.initials: A
authors.lastname: Dolganiuc
authors.forename: Karen
authors.initials: K
authors.lastname: Kodys
authors.forename: Evelyn
authors.initials: E
authors.lastname: Kurt-Jones
authors.forename: Gyongyi
authors.initials: G
authors.lastname: Szabo
mesh_terms: D000818:Animals; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D004195:Disease Models, Animal; D000431:Ethanol; D005234:Fatty Liver / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D051218:Lymphocyte Antigen 96 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D018950:Lipopolysaccharide Receptors; C411728:Ly96 protein, mouse; D051218:Lymphocyte Antigen 96; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D017382:Reactive Oxygen Species; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; D009249:NADP; D019392:Cytochrome P-450 CYP2E1
references.citation: Biochem J. 2007 May 1;403(3):451-61
references.pmid: 17217339
references.citation: Gastroenterology. 2003 Mar;124(3):778-90
references.pmid: 12612915
references.citation: J Leukoc Biol. 2006 Jun;79(6):1348-56
references.pmid: 16554353
references.citation: J Immunol. 2005 Nov 1;175(9):5596-600
references.pmid: 16237045
references.citation: Hepatology. 2006 Jul;44(1):263-74
references.pmid: 16799984
references.citation: J Immunol. 2002 Mar 15;168(6):2963-9
references.pmid: 11884468
references.citation: J Immunol. 2001 Apr 1;166(7):4737-42
references.pmid: 11254735
references.citation: Hepatology. 2006 Aug;44(2):287-98
references.pmid: 16871558
references.citation: Gastroenterology. 2007 Feb;132(2):687-97
references.pmid: 17258719
references.citation: Nat Rev Immunol. 2007 May;7(5):353-64
references.pmid: 17457343
references.citation: Hepatology. 2006 Feb;43(2 Suppl 1):S63-74
references.pmid: 16447273
references.citation: J Biol Chem. 2002 Mar 15;277(11):9103-11
references.pmid: 11781315
references.citation: Nat Immunol. 2005 Jun;6(6):565-70
references.pmid: 15895089
references.citation: Biochem J. 2007 Jul 15;405(2):251-9
references.pmid: 17407446
references.citation: J Clin Invest. 2000 Oct;106(7):867-72
references.pmid: 11018074
references.citation: Alcohol Clin Exp Res. 2002 Aug;26(8 Suppl):6S-10S
references.pmid: 12198367
references.citation: J Biol Chem. 1996 Sep 20;271(38):23445-51
references.pmid: 8798551
references.citation: Alcohol. 2002 May;27(1):13-5
references.pmid: 12062631
references.citation: Alcohol Clin Exp Res. 2005 Jun;29(6):1018-26
references.pmid: 15976528
references.citation: Alcohol Clin Exp Res. 2005 Nov;29(11 Suppl):166S-71S
references.pmid: 16344604
references.citation: Hepatology. 2001 Jul;34(1):101-8
references.pmid: 11431739
references.citation: Trends Biochem Sci. 2003 Sep;28(9):502-8
references.pmid: 13678962
references.citation: Hepatology. 2000 Apr;31(4):932-6
references.pmid: 10733550
references.citation: Alcohol. 2004 May;33(1):17-30
references.pmid: 15353170
references.citation: Gastroenterology. 1999 Oct;117(4):942-52
references.pmid: 10500078
references.citation: J Immunol. 2004 Sep 15;173(6):3589-93
references.pmid: 15356101
references.citation: Gastroenterology. 2006 Jul;131(1):272-5
references.pmid: 16831609
references.citation: Gastroenterology. 2005 Jun;128(7):2066-76
references.pmid: 15940638
references.citation: Gastroenterology. 2003 Dec;125(6):1834-44
references.pmid: 14724835
references.citation: Mol Cell Biol. 2006 Jan;26(1):140-54
references.pmid: 16354686
references.citation: Hepatology. 2004 Aug;40(2):376-85
references.pmid: 15368442
references.citation: J Leukoc Biol. 2004 Oct;76(4):760-81
references.pmid: 15240752
references.citation: Am J Physiol Gastrointest Liver Physiol. 2006 Oct;291(4):G681-8
references.pmid: 16751174
references.citation: Gene. 2001 May 16;269(1-2):131-40
references.pmid: 11376945
references.citation: Toxicol Appl Pharmacol. 2006 Oct 1;216(1):1-10
references.pmid: 16712892
references.citation: Semin Immunol. 2004 Feb;16(1):3-9
references.pmid: 14751757
references.citation: J Immunol. 2007 Jan 15;178(2):1164-71
references.pmid: 17202381
references.citation: Liver Int. 2006 Nov;26(9):1021-8
references.pmid: 17032401
references.citation: J Biol Chem. 1992 Jan 5;267(1):467-72
references.pmid: 1730609
references.citation: Liver Transpl Surg. 1997 May;3(3):197-350
references.pmid: 9377762
references.citation: Alcohol Res Health. 2003;27(4):300-6
references.pmid: 15540801
references.citation: Immunology. 2004 Oct;113(2):153-62
references.pmid: 15379975
references.citation: Semin Immunol. 2007 Feb;19(1):24-32
references.pmid: 17275323