Pattern recognition receptors: A contemporary view on liver diseases

Pattern recognition receptors (PRRs) function as sensors of microbial danger signals enabling the vertebrate host to initiate an immune response. PRRs are present not only in immune cells but also in liver parenchymal cells and the complexity of the cell populations provide unique aspects to pathogen recognition and tissue damage in the liver. This review discusses the role of different PRRs in pathogen recognition in the liver, and focuses on the role of PRRs in hepatic inflammation, cholestasis, ischemia, repair and fibrosis. PRRs as novel therapeutic targets are evaluated. (HEPATOLOGY 2006;44:287–298.)

[1]  T. Asselah,et al.  Cytokines as predictors for sustained response and as markers for immunomodulation in patients with chronic hepatitis C. , 2001, Clinical biochemistry.

[2]  N. LaRusso,et al.  Multiple TLRs Are Expressed in Human Cholangiocytes and Mediate Host Epithelial Defense Responses to Cryptosporidium parvum via Activation of NF-κB1 , 2005, The Journal of Immunology.

[3]  G. Trinchieri,et al.  Human TLR10 Is a Functional Receptor, Expressed by B Cells and Plasmacytoid Dendritic Cells, Which Activates Gene Transcription through MyD881 , 2005, The Journal of Immunology.

[4]  S. Lemon,et al.  Control of antiviral defenses through hepatitis C virus disruption of retinoic acid-inducible gene-I signaling. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[5]  I. Rusyn,et al.  Diphenyleneiodonium sulfate, an NADPH oxidase inhibitor, prevents early alcohol-induced liver injury in the rat. , 2001, American journal of physiology. Gastrointestinal and liver physiology.

[6]  L. Romics,et al.  Diverse regulation of NF‐κB and peroxisome proliferator‐activated receptors in murine nonalcoholic fatty liver , 2004, Hepatology.

[7]  F. Gao,et al.  Toll‐Like Receptor and Heme Oxygenase‐1 Signaling in Hepatic Ischemia/Reperfusion Injury , 2005, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[8]  F. Chisari,et al.  Toll-Like Receptor Signaling Inhibits Hepatitis B Virus Replication In Vivo , 2005, Journal of Virology.

[9]  F. Re,et al.  Importance of extra- and intracellular domains of TLR1 and TLR2 in NFκB signaling , 2003, The Journal of cell biology.

[10]  S. Akira,et al.  Requirement for TLR9 in the Immunomodulatory Activity of Propionibacterium acnes1 , 2005, The Journal of Immunology.

[11]  G. Su,et al.  Impaired Hepatocyte Regeneration in Toll-Like Receptor 4 Mutant Mice , 2004, Digestive Diseases and Sciences.

[12]  J. Spitzer,et al.  Hepatic sinusoidal endothelial cell in alcoholemia and endotoxemia. , 1996, Alcoholism, clinical and experimental research.

[13]  A. Visintin,et al.  Secreted MD-2 is a large polymeric protein that efficiently confers lipopolysaccharide sensitivity to Toll-like receptor 4 , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[14]  T. Berg,et al.  Isatoribine, an agonist of TLR7, reduces plasma virus concentration in chronic hepatitis C infection , 2005, Hepatology.

[15]  M. Fenton,et al.  TLRs: differential adapter utilization by toll-like receptors mediates TLR-specific patterns of gene expression. , 2003, Molecular interventions.

[16]  U. Böcker,et al.  Differential expression of toll-like receptors 2 and 4 in patients with liver cirrhosis , 2003, European journal of gastroenterology & hepatology.

[17]  E. Bock,et al.  Novel role of toll-like receptor 3 in hepatitis C-associated glomerulonephritis. , 2006, The American journal of pathology.

[18]  D. Brenner,et al.  Alcohol causes both tolerance and sensitization of rat Kupffer cells via mechanisms dependent on endotoxin. , 1998, Gastroenterology.

[19]  M. Gale,et al.  CARD games between virus and host get a new player. , 2006, Trends in immunology.

[20]  B. Beutler,et al.  Sepsis and evolution of the innate immune response. , 2001, Critical care medicine.

[21]  R. Purcell,et al.  Viral and immunological determinants of hepatitis C virus clearance, persistence, and disease , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[22]  S. Akira,et al.  Lymphoid follicle destruction and immunosuppression after repeated CpG oligodeoxynucleotide administration , 2004, Nature Medicine.

[23]  P. Lambert,et al.  Co-administration of CpG oligonucleotides enhances the late affinity maturation process of human anti-hepatitis B vaccine response. , 2004, Vaccine.

[24]  Antonio Lanzavecchia,et al.  Specialization and complementarity in microbial molecule recognition by human myeloid and plasmacytoid dendritic cells , 2001, European journal of immunology.

[25]  Michael Karin,et al.  NF-kappaB: linking inflammation and immunity to cancer development and progression. , 2005, Nature reviews. Immunology.

[26]  J. Metzger,et al.  Toll‐like receptor 9 binds single‐stranded CpG‐DNA in a sequence‐ and pH‐dependent manner , 2004, European journal of immunology.

[27]  Kai Wei,et al.  Effects of lipopolysaccharides stimulated Kupffer cells on activation of rat hepatic stellate cells. , 2004, World journal of gastroenterology.

[28]  T. Seya,et al.  Antibodies against human Toll-like receptors (TLRs): TLR distribution and localization in human dendritic cells , 2005, Journal of endotoxin research.

[29]  Christian Jobin,et al.  Toll‐Like receptor 4 mediates inflammatory signaling by bacterial lipopolysaccharide in human hepatic stellate cells , 2003, Hepatology.

[30]  Jidong Cheng,et al.  Recombinant HBsAg inhibits LPS-induced COX-2 expression and IL-18 production by interfering with the NFkappaB pathway in a human monocytic cell line, THP-1. , 2005, Journal of hepatology.

[31]  Shizuo Akira,et al.  Innate immune recognition of viral infection , 2006, Nature Immunology.

[32]  M. Lotze,et al.  Hepatic Ischemia/Reperfusion Injury Involves Functional TLR4 Signaling in Nonparenchymal Cells1 , 2005, The Journal of Immunology.

[33]  B. Gao,et al.  Host factors and failure of interferon-alpha treatment in hepatitis C virus. , 2004, Hepatology.

[34]  S. Akira,et al.  A Toll-like receptor recognizes bacterial DNA , 2000, Nature.

[35]  D. Golenbock,et al.  Human Cytomegalovirus Activates Inflammatory Cytokine Responses via CD14 and Toll-Like Receptor 2 , 2003, Journal of Virology.

[36]  Z. Zhai,et al.  VISA Is an Adapter Protein Required for Virus-Triggered IFN-β Signaling , 2005 .

[37]  B. Beutler,et al.  Inferences, questions and possibilities in Toll-like receptor signalling , 2004, Nature.

[38]  R. Sun,et al.  Toll-like receptor 3 ligand attenuates LPS-induced liver injury by down-regulation of toll-like receptor 4 expression on macrophages. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[39]  S. Akira,et al.  Sequence-specific potent induction of IFN-α by short interfering RNA in plasmacytoid dendritic cells through TLR7 , 2005, Nature Medicine.

[40]  Charles A. Janeway,et al.  IRAK-M Is a Negative Regulator of Toll-like Receptor Signaling , 2002, Cell.

[41]  S. Akira,et al.  Species-Specific Recognition of Single-Stranded RNA via Toll-like Receptor 7 and 8 , 2004, Science.

[42]  D. Davies,et al.  Leucine-rich repeats and pathogen recognition in Toll-like receptors. , 2003, Trends in immunology.

[43]  Stanley M Lemon,et al.  Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the Toll-like receptor 3 adaptor protein TRIF. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[44]  S. Akira,et al.  Toll-like receptor–independent gene induction program activated by mammalian DNA escaped from apoptotic DNA degradation , 2005, The Journal of experimental medicine.

[45]  Shizuo Akira,et al.  Toll/IL-1 Receptor Domain-Containing Adaptor Inducing IFN-β (TRIF) Associates with TNF Receptor-Associated Factor 6 and TANK-Binding Kinase 1, and Activates Two Distinct Transcription Factors, NF-κB and IFN-Regulatory Factor-3, in the Toll-Like Receptor Signaling 1 , 2003, The Journal of Immunology.

[46]  F. Chisari,et al.  Relative Sensitivity of Hepatitis B Virus and Other Hepatotropic Viruses to the Antiviral Effects of Cytokines , 2000, Journal of Virology.

[47]  R. Sun,et al.  Negative regulation of liver regeneration by innate immunity (natural killer cells/interferon-gamma). , 2004, Gastroenterology.

[48]  C. Coban,et al.  A Toll-like receptor–independent antiviral response induced by double-stranded B-form DNA , 2006, Nature Immunology.

[49]  S. Seki,et al.  An experimentally-induced acute hepatic failure model in various strains of mice , 1989, Gastroenterologia Japonica.

[50]  B. Monks,et al.  Pharmacological Inhibition of Endotoxin Responses Is Achieved by Targeting the TLR4 Coreceptor, MD-21 , 2005, The Journal of Immunology.

[51]  Z. Zhai,et al.  VISA is an adapter protein required for virus-triggered IFN-beta signaling. , 2005, Molecular cell.

[52]  B. Gao,et al.  Host factors and failure of interferon‐α treatment in hepatitis C virus , 2004 .

[53]  Masahiro Ito,et al.  Hepatic expression of toll-like receptor 4 in primary biliary cirrhosis. , 2005, Journal of autoimmunity.

[54]  J. Williams.  Carbon tetrachloride hepatotoxicity in endotoxin tolerant and polymyxin B-treated rats. , 1988, International journal of immunopharmacology.

[55]  L. Romics,et al.  Increased lipopolysaccharide sensitivity in alcoholic fatty livers is independent of leptin deficiency and toll-like receptor 4 (TLR4) or TLR2 mRNA expression. , 2005, Alcoholism, clinical and experimental research.

[56]  Ryan M. O’Connell,et al.  Cutting Edge: TLR4 Activation Mediates Liver Ischemia/Reperfusion Inflammatory Response via IFN Regulatory Factor 3-Dependent MyD88-Independent Pathway1 , 2004, The Journal of Immunology.

[57]  M. Katze,et al.  To interfere and to anti-interfere: the interplay between hepatitis C virus and interferon. , 2002, Viral immunology.

[58]  L. Romics,et al.  Acute alcohol inhibits the induction of nuclear regulatory factor kappa B activation through CD14/toll-like receptor 4, interleukin-1, and tumor necrosis factor receptors: a common mechanism independent of inhibitory kappa B alpha degradation? , 2002, Alcoholism, clinical and experimental research.

[59]  K. Tanamoto,et al.  Deacylation of bacterial lipopolysaccharide in rat hepatocytes in vitro. , 1989, British journal of experimental pathology.

[60]  S. Foster,et al.  An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid , 2003, Nature Immunology.

[61]  S. Lemon,et al.  Distinct Poly(I-C) and Virus-activated Signaling Pathways Leading to Interferon-β Production in Hepatocytes* , 2005, Journal of Biological Chemistry.

[62]  William M. Lee,et al.  Viral and therapeutic control of IFN-beta promoter stimulator 1 during hepatitis C virus infection. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[63]  S. Akira,et al.  Inhibition of RIG-I-Dependent Signaling to the Interferon Pathway during Hepatitis C Virus Expression and Restoration of Signaling by IKKε , 2005, Journal of Virology.

[64]  C. Klaassen,et al.  Endotoxin pretreatment protects against the hepatotoxicity of acetaminophen and carbon tetrachloride: role of cytochrome P450 suppression. , 2000, Toxicology.

[65]  S. Dower,et al.  Regulation of Toll-Like Receptors in Human Monocytes and Dendritic Cells1 , 2001, The Journal of Immunology.

[66]  Michael Karin,et al.  IKKβ Couples Hepatocyte Death to Cytokine-Driven Compensatory Proliferation that Promotes Chemical Hepatocarcinogenesis , 2005, Cell.

[67]  D. Golenbock,et al.  Hepatitis C core and nonstructural 3 proteins trigger toll-like receptor 2-mediated pathways and inflammatory activation. , 2004, Gastroenterology.

[68]  D. Golenbock,et al.  Toll‐like receptor 2 mediates inflammatory cytokine induction but not sensitization for liver injury by Propioni‐ bacterium acnes , 2005, Journal of leukocyte biology.

[69]  T. Seya,et al.  Surface-Expressed TLR6 Participates in the Recognition of Diacylated Lipopeptide and Peptidoglycan in Human Cells1 , 2005, The Journal of Immunology.

[70]  Tomoki Ito,et al.  Roles of toll-like receptors in natural interferon-producing cells as sensors in immune surveillance. , 2002, Human immunology.

[71]  S. Akira,et al.  TLR signaling. , 2006, Current topics in microbiology and immunology.

[72]  C. Ferrari,et al.  Immunopathogenesis of hepatitis C virus infection. , 1999, Journal of hepatology.

[73]  K. Isse,et al.  Interferon γ accelerates NF-κB activation of biliary epithelial cells induced by Toll-like receptor and ligand interaction , 2006, Journal of Clinical Pathology.

[74]  L. Morrison.  The Toll of herpes simplex virus infection. , 2004, Trends in microbiology.

[75]  Ralf Bartenschlager,et al.  Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus , 2005, Nature.

[76]  M. Woodle,et al.  Harnessing in vivo siRNA delivery for drug discovery and therapeutic development , 2006, Drug Discovery Today.

[77]  S. Akira,et al.  Contribution of Toll‐like receptor/myeloid differentiation factor 88 signaling to murine liver regeneration , 2005, Hepatology.

[78]  E. Kovacs,et al.  In Vivo Ethanol Exposure Down-Regulates TLR2-, TLR4-, and TLR9-Mediated Macrophage Inflammatory Response by Limiting p38 and ERK1/2 Activation1 , 2005, The Journal of Immunology.

[79]  T. Bártfai,et al.  A low molecular weight mimic of the Toll/IL-1 receptor/resistance domain inhibits IL-1 receptor-mediated responses , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[80]  J. Spitzer,et al.  Acute ethanol intoxication prevents lipopolysaccharide-induced down regulation of protein kinase C in rat Kupffer cells. , 1992, Alcoholism, clinical and experimental research.

[81]  Y. Vodovotz,et al.  The hepatocyte as a microbial product-responsive cell , 2001, Journal of endotoxin research.

[82]  Jean S. Campbell,et al.  Proinflammatory Cytokine Production in Liver Regeneration Is Myd88-Dependent, but Independent of Cd14, Tlr2, and Tlr41 , 2006, The Journal of Immunology.

[83]  S. Akira,et al.  Pathogen Recognition and Innate Immunity , 2006, Cell.

[84]  Kyu-Jin Park,et al.  Hepatitis C Virus NS5A Protein Modulates c-Jun N-terminal Kinase through Interaction with Tumor Necrosis Factor Receptor-associated Factor 2* , 2003, Journal of Biological Chemistry.

[85]  S. Goyert,et al.  Reduced Early Alcohol-Induced Liver Injury in CD14-Deficient Mice1 , 2001, The Journal of Immunology.

[86]  O. Bulbena,et al.  Increased serum nitrite and nitrate levels in patients with cirrhosis: Relationship to endotoxemia , 1993, Hepatology.

[87]  J. Pawlotsky,et al.  Mechanisms of antiviral treatment efficacy and failure in chronic hepatitis C. , 2003, Antiviral research.

[88]  A. Dolganiuc,et al.  Critical role of toll-like receptors and the common TLR adaptor, MyD88, in induction of granulomas and liver injury. , 2006, Journal of hepatology.

[89]  H. Harris,et al.  Hepatic endosomal trafficking of lipoprotein-bound endotoxin in rats. , 2002, The Journal of surgical research.

[90]  F. Gusovsky,et al.  Toll-like Receptor-4 Mediates Lipopolysaccharide-induced Signal Transduction* , 1999, The Journal of Biological Chemistry.

[91]  J. Inoue,et al.  TRAF6‐NF‐κB pathway is essential for interleukin‐1‐induced TLR2 expression and its functional response to TLR2 ligand in murine hepatocytes , 2003, Immunology.

[92]  C. Coban,et al.  Interferon-α induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6 , 2004, Nature Immunology.

[93]  Roger Williams,et al.  Peripheral blood mononuclear cell expression of toll‐like receptors and relation to cytokine levels in cirrhosis , 2003, Hepatology.

[94]  N. Kato,et al.  Interaction between the HCV NS3 protein and the host TBK1 protein leads to inhibition of cellular antiviral responses , 2005, Hepatology.

[95]  H. Park,et al.  Cutting Edge: Direct Interaction of TLR4 with NAD(P)H Oxidase 4 Isozyme Is Essential for Lipopolysaccharide-Induced Production of Reactive Oxygen Species and Activation of NF-κB1 , 2004, The Journal of Immunology.

[96]  M. Ojaniemi,et al.  TLR-2 is upregulated and mobilized to the hepatocyte plasma membrane in the space of Disse and to the Kupffer cells TLR-4 dependently during acute endotoxemia in mice. , 2006, Immunology letters.

[97]  Zhijian J. Chen,et al.  Identification and Characterization of MAVS, a Mitochondrial Antiviral Signaling Protein that Activates NF-κB and IRF3 , 2005, Cell.

[98]  岡部 泰賢.  Toll-like receptor-independent gene induction program activated by mammalian DNA escaped from apoptotic DNA degradation , 2006 .

[99]  S. Akira,et al.  TRAM is specifically involved in the Toll-like receptor 4–mediated MyD88-independent signaling pathway , 2003, Nature Immunology.

[100]  M. Nishimura,et al.  Tissue-specific mRNA expression profiles of human toll-like receptors and related genes. , 2005, Biological & pharmaceutical bulletin.

[101]  K. Honda,et al.  Role of a transductional-transcriptional processor complex involving MyD88 and IRF-7 in Toll-like receptor signaling. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[102]  N. Horiike,et al.  Early development of primary biliary cirrhosis in female C57BL/6 mice because of poly I:C administration , 2005, Liver international : official journal of the International Association for the Study of the Liver.

[103]  P. Brun,et al.  Exposure to bacterial cell wall products triggers an inflammatory phenotype in hepatic stellate cells. , 2005, American journal of physiology. Gastrointestinal and liver physiology.

[104]  I. Haga,et al.  The role of Toll-like receptors in the host response to viruses. , 2005, Molecular immunology.

[105]  R. Bartenschlager,et al.  Hepatitis C virus RNA replication is resistant to tumour necrosis factor-α , 2003 .

[106]  P. Godowski,et al.  Tissue Expression of Human Toll-Like Receptors and Differential Regulation of Toll-Like Receptor mRNAs in Leukocytes in Response to Microbes, Their Products, and Cytokines , 2002, The Journal of Immunology.

[107]  D. Philpott,et al.  TIR, CARD and PYRIN: three domains for an antimicrobial triad , 2006, Cell Death and Differentiation.

[108]  C. Coban,et al.  Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR)7- and TLR9-mediated interferon-α induction , 2005, The Journal of experimental medicine.

[109]  S. Akira,et al.  MyD88 as a bottle neck in Toll/IL-1 signaling. , 2002, Current topics in microbiology and immunology.

[110]  A. Craxì,et al.  Clinical trial results of peginterferons in combination with ribavirin. , 2003, Seminars in liver disease.

[111]  S. Akira,et al.  Toll-like Receptor 9–mediated Recognition of Herpes Simplex Virus-2 by Plasmacytoid Dendritic Cells , 2003, The Journal of experimental medicine.

[112]  Kay Hofmann,et al.  RIP1 is an essential mediator of Toll-like receptor 3-induced NF-kappa B activation. , 2004, Nature immunology.

[113]  Yu-Tseung Liu,et al.  Activation of anti-hepatitis C virus responses via Toll-like receptor 7. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[114]  L. Nagy.  Recent Insights into the Role of the Innate Immune System in the Development of Alcoholic Liver Disease , 2003, Experimental biology and medicine.

[115]  S. Akira,et al.  Role of Adaptor TRIF in the MyD88-Independent Toll-Like Receptor Signaling Pathway , 2003, Science.

[116]  S. Akira,et al.  Lipopolysaccharide Stimulates the MyD88-Independent Pathway and Results in Activation of IFN-Regulatory Factor 3 and the Expression of a Subset of Lipopolysaccharide-Inducible Genes1 , 2001, The Journal of Immunology.

[117]  Osamu Takeuchi,et al.  IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction , 2005, Nature Immunology.

[118]  Simon C Watkins,et al.  Normal rat hepatic stellate cells respond to endotoxin in LBP‐independent manner to produce inhibitor(s) of DNA synthesis in hepatocytes , 2005, Journal of cellular physiology.

[119]  R. Medzhitov,et al.  Toll-like receptors: balancing host resistance with immune tolerance. , 2003, Current opinion in immunology.

[120]  A. Dunne,et al.  Adaptor usage and Toll‐like receptor signaling specificity , 2005, FEBS letters.

[121]  G. Gerken,et al.  Human Kupffer cells secrete IL-10 in response to lipopolysaccharide (LPS) challenge. , 1995, Journal of hepatology.

[122]  Q. Zheng,et al.  Suppression of Innate Immunity by Acute Ethanol Administration: A Global Perspective and a New Mechanism Beginning with Inhibition of Signaling through TLR31 , 2004, The Journal of Immunology.

[123]  A. Dolganiuc,et al.  Subversion of plasmacytoid and myeloid dendritic cell functions in chronic HCV infection. , 2005, Immunobiology.

[124]  D. Rossignol,et al.  E5531, a synthetic non‐toxic lipid A derivative blocks the immunobiological activities of lipopolysaccharide , 1999, British journal of pharmacology.

[125]  S. Akira,et al.  Toll-like receptors in innate immunity. , 2004, International immunology.

[126]  Stefan Bauer,et al.  Antagonistic antibody prevents toll-like receptor 2-driven lethal shock-like syndromes. , 2004, The Journal of clinical investigation.

[127]  Y. Nagakawa,et al.  Lipopolysaccharides induced increases in Fas ligand expression by Kupffer cells via mechanisms dependent on reactive oxygen species. , 2004, American journal of physiology. Gastrointestinal and liver physiology.

[128]  J. Lifson,et al.  CpG oligodeoxynucleotides improve the response to hepatitis B immunization in healthy and SIV-infected rhesus macaques , 2004, AIDS.

[129]  S. Akira,et al.  The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5 , 2001, Nature.

[130]  L. Romics,et al.  Acute Alcohol Inhibits the Induction of Nuclear Regulatory Factor κB Activation Through CD14/Toll‐Like Receptor 4, Interleukin‐1, and Tumor Necrosis Factor Receptors: A Common Mechanism Independent of Inhibitory κBα Degradation? , 2002 .

[131]  T. Giese,et al.  Quantitative Expression of Toll-Like Receptor 1–10 mRNA in Cellular Subsets of Human Peripheral Blood Mononuclear Cells and Sensitivity to CpG Oligodeoxynucleotides1 , 2002, The Journal of Immunology.

[132]  M. Neurath,et al.  Development and functional consequences of LPS tolerance in sinusoidal endothelial cells of the liver , 2005, Journal of leukocyte biology.

[133]  N. Sawada,et al.  p38 MAP-kinase regulates function of gap and tight junctions during regeneration of rat hepatocytes. , 2005, Journal of hepatology.

[134]  Shizuo Akira,et al.  Innate Antiviral Responses by Means of TLR7-Mediated Recognition of Single-Stranded RNA , 2004, Science.

[135]  T. Giese,et al.  Toll-like receptor expression reveals CpG DNA as a unique microbial stimulus for plasmacytoid dendritic cells which synergizes with CD40 ligand to induce high amounts of IL-12. , 2001, European journal of immunology.

[136]  A. Yamamoto,et al.  Subcellular Localization of Toll-Like Receptor 3 in Human Dendritic Cells , 2003, The Journal of Immunology.

[137]  H. K. Bojes,et al.  Inactivation of Kupffer cells prevents early alcohol‐induced liver injury , 1994, Hepatology.

[138]  S. Akira,et al.  Cellular responses to bacterial cell wall components are mediated through MyD88-dependent signaling cascades. , 2000, International immunology.

[139]  Zhijian J. Chen,et al.  Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. , 2005, Cell.

[140]  Jenny Kim.  Review of the Innate Immune Response in Acne vulgaris: Activation of Toll-Like Receptor 2 in Acne Triggers Inflammatory Cytokine Responses , 2005, Dermatology.

[141]  M. Chamaillard,et al.  NOD-LRR proteins: role in host-microbial interactions and inflammatory disease. , 2005, Annual review of biochemistry.

[142]  S. Sakamoto,et al.  Novel roles of TLR3 tyrosine phosphorylation and PI3 kinase in double-stranded RNA signaling , 2004, Nature Structural &Molecular Biology.

[143]  Y. Shoenfeld,et al.  Toll-like Receptors and their Role in the Development of Autoimmune Diseases , 2004, Autoimmunity.

[144]  Masahiro Ito,et al.  Enhanced expression of type I interferon and toll-like receptor-3 in primary biliary cirrhosis , 2005, Laboratory Investigation.

[145]  Elisabeth L. Humphris,et al.  Role of Toll-Like Receptors in Changes in Gene Expression and NF-κB Activation in Mouse Hepatocytes Stimulated with Lipopolysaccharide , 2002, Infection and Immunity.

[146]  Helen Y Wang,et al.  Regulatory T cells and Toll-like receptors in tumor immunity. , 2006, Seminars in immunology.

[147]  S. Akira,et al.  Cutting Edge: A Novel Toll/IL-1 Receptor Domain-Containing Adapter That Preferentially Activates the IFN-β Promoter in the Toll-Like Receptor Signaling1 , 2002, The Journal of Immunology.

[148]  Zhengfan Jiang,et al.  CD14 is required for MyD88-independent LPS signaling , 2005, Nature Immunology.

[149]  L. Romics,et al.  Selective priming to Toll‐like receptor 4 (TLR4), not TLR2, ligands by P. acnes involves up‐regulation of MD‐2 in mice , 2004, Hepatology.

[150]  G. Arteel,et al.  Toll‐like receptor 4 is involved in the mechanism of early alcohol‐induced liver injury in mice , 2001, Hepatology.

[151]  Daniel R. Caffrey,et al.  LPS-TLR4 Signaling to IRF-3/7 and NF-κB Involves the Toll Adapters TRAM and TRIF , 2003, The Journal of experimental medicine.

[152]  Chung,et al.  Genes, Receptors, Signals and Responses to Lipopolysaccharide Endotoxin , 2000, Scandinavian journal of immunology.

[153]  R. Flavell,et al.  Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3 , 2001, Nature.

[154]  E. Schiff,et al.  Treatment of HCV: approach to difficult cases. , 1997, Clinics in liver disease.

[155]  P. Godowski,et al.  Toll-like receptor 2–mediated NF-κB activation requires a Rac1-dependent pathway , 2000, Nature Immunology.

[156]  K. Isse,et al.  Lipopolysaccharide Activates Nuclear Factor-KappaB through Toll-Like Receptors and Related Molecules in Cultured Biliary Epithelial Cells , 2003, Laboratory Investigation.

[157]  J. Fung,et al.  Activation of the lipopolysaccharide signaling pathway in hepatic transplantation preservation injury12 , 2002, Transplantation.

[158]  M. Kaplan,et al.  Bacterial CpG induces hyper-IgM production in CD27(+) memory B cells in primary biliary cirrhosis. , 2005, Gastroenterology.

[159]  K. Tracey,et al.  The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion , 2005, The Journal of experimental medicine.

[160]  A. Shahangian,et al.  Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response , 2006, Nature.

[161]  H. Wagner,et al.  All is not Toll: new pathways in DNA recognition , 2006, The Journal of experimental medicine.

[162]  P. Galle,et al.  HSP60 and CpG-DNA-oligonucleotides differentially regulate LPS-tolerance of hepatic Kupffer cells. , 2004, Immunology letters.

[163]  R. Vabulas,et al.  Bacterial CpG‐DNA and lipopolysaccharides activate Toll‐like receptors at distinct cellular compartments , 2002, European journal of immunology.

[164]  Shizuo Akira,et al.  TIR domain-containing adaptors regulate TLR signaling pathways. , 2005, Advances in experimental medicine and biology.

[165]  Z. Spolarics.  Endotoxin stimulates gene expression of ROS-eliminating pathways in rat hepatic endothelial and Kupffer cells. , 1996, The American journal of physiology.

[166]  S. Vogel,et al.  Inhibition of Lipopolysaccharide-Induced Signal Transduction in Endotoxin-Tolerized Mouse Macrophages: Dysregulation of Cytokine, Chemokine, and Toll-Like Receptor 2 and 4 Gene Expression1 , 2000, The Journal of Immunology.

[167]  A. Marshak‐Rothstein,et al.  Toll‐like receptors, endogenous ligands, and systemic autoimmune disease , 2005, Immunological reviews.