No longer an innocent bystander: Epithelial toll-like receptor signaling in the development of mucosal inflammation

Molecular Medicine

Volumn 14, Issue 9-10, 2008, Pages 645-659

  Gribar, Steven C ^a   Richardson, Ward M ^a   Sodhi, Chhinder P ^a   Hackam, David J ^a  

^a CHILDREN S HOSPITAL OF PITTSBURGH   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

6 [N (2 CHLORO 4 FLUOROPHENYL)SULFAMOYL] 1 CYCLOHEXENE 1 CARBOXYLIC ACID ETHYL ESTER; ANTIINFLAMMATORY AGENT; PHOSPHATE; PROTEIN A52R; ST 2825; TOLL LIKE RECEPTOR; UNCLASSIFIED DRUG; VIRUS PROTEIN;

ANTIINFLAMMATORY ACTIVITY; CELL ACTIVATION; CELL COMMUNICATION; CELL DAMAGE; CELL FUNCTION; CELL INTERACTION; CELL REGENERATION; CONTROLLED STUDY; ENDOTOXEMIA; ENTERITIS; EPITHELIUM CELL; HOMEOSTASIS; IMMUNE SYSTEM; INNATE IMMUNITY; INTESTINE EPITHELIUM CELL; KIDNEY; LUNG; MUCOSA; MUCOSA INFLAMMATION; NEPHRITIS; NONHUMAN; PATHOGENESIS; PNEUMONIA; PRIORITY JOURNAL; PROTEIN EXPRESSION; REVIEW; SEPSIS; SIGNAL TRANSDUCTION;

EPITHELIAL CELLS; GENE EXPRESSION REGULATION; HUMANS; INFLAMMATION; INTESTINAL DISEASES; INTESTINAL MUCOSA; MUCOUS MEMBRANE; RESPIRATORY SYSTEM; RESPIRATORY TRACT DISEASES; SIGNAL TRANSDUCTION; TOLL-LIKE RECEPTORS;

EID: 55049110418     PISSN: 10761551     EISSN: None     Source Type: Journal    
DOI: 10.2119/2008-00035.Gribar     Document Type: Review

References (199)

1. Bibiloni R, Mangold M, Madsen KL, Fedorak RN, Tannock GW. (2006) The bacteriology of biopsies differs between newly diagnosed, untreated, Crohn's disease and ulcerative colitis patients. J. Med. Microbiol. 55:1141-9.
2. Martinez-Medina M, Aldeguer X, Gonzalez-Huix F, Acero D, Garcia-Gil LJ. (2006) Abnormal microbiota composition in the ileocolonic mucosa of Crohn's disease patients as revealed by polymerase chain reaction-denaturing gradient gel electrophoresis. Inflamm. Bowel Dis. 12:1136-45.
3. Xavier RJ, Podolsky DK. (2007) Unravelling the pathogenesis of inflammatory bowel disease. Nature 448:427-34.
4. Anand R, Leaphart CL, Mollen K, Hackam D. (2007) The role of the intestinal barrier in the pathogenesis of necrotizing enterocolitis. Shock 27:124-33.
5. Hippenstiel S, Opitz B, Schmeck B, Suttorp N. (2006) Lung epithelium as a sentinel and effector system in pneumonia-molecular mechanisms of pathogen recognition and signal transduction. Respir. Res. 7:97.
6. Holgate ST. (2007) Epithelium dysfunction in asthma. J. Allergy Clin. Immunol. 120:1233-44; quiz 1245-36.
7. Sigurs N, Bjarnason R, Sigurbergsson F, Kjellman B. (2000) Respiratory syncytial virus bronchiolitis in infancy is an important risk factor for asthma and allergy at age 7. Am. J. Respir. Crit. Care Med. 161:1501-7.
8. Bonventre JV, Zuk A. (2004) Ischemic acute renal failure: an inflammatory disease? Kidney Int. 66:480-5.
9. Parsons CL. (2007) The role of the urinary epithelium in the pathogenesis of interstitial cystitis/prostatitis/urethritis. Urology 69:9-16.
10. Haraoka M, et al. (1999) Neutrophil recruitment and resistance to urinary tract infection. J. Infect. Dis. 180:1220-9.
11. Lewis K, et al. (2008) Decreased epithelial barrier function evoked by exposure to metabolic stress and nonpathogenic E. coli is enhanced by TNF-alpha. Am. J. Physiol. 294:G669-78.
12. Cleret A, et al. (2007) Lung dendritic cells rapidly mediate anthrax spore entry through the pulmonary route. J. Immunol. 178:7994-8001.
13. Frank JA, Wray CM, McAuley DF, Schwendener R, Matthay MA. (2006) Alveolar macrophages contribute to alveolar barrier dysfunction in ventilator-induced lung injury. Am. J. Physiol. 291:L1191-8.
14. Rachmilewitz D, et al. (2004) Toll-like receptor 9 signaling mediates the anti-inflammatory effects of probiotics in murine experimental colitis. Gastroenterology 126:520-8.
15. Mayer AK, et al. (2007) Differential recognition of TLR-dependent microbial ligands in human bronchial epithelial cells. J. Immunol. 178:3134-42.
16. Andersen-Nissen E, et al. (2007) Cutting edge: Tlr5-/- mice are more susceptible to Escherichia coli urinary tract infection. J. Immunol. 178:4717-20.
17. Sappington P, et al. (2002) HMGB1 B box increases the permeability of Caco-2 enterocytic monolayers and impairs intestinal barrier function in mice. Gastroenterology 123:790-802.
18. Jiang D, et al. (2005) Regulation of lung injury and repair by Toll-like receptors and hyaluronan. Nat. Med. 11:1173-9.
19. Boodoo S, Spannhake EW, Powell JD, Horton MR. (2006) Differential regulation of hyaluronan-induced IL-8 and IP-10 in airway epithelial cells. Am. J. Physiol. 291:L479-86.
20. Uematsu S, Akira S. (2008) Toll-Like receptors (TLRs) and their ligands. Handb. Exp. Pharmacol. 1-20.
21. Kawai T, Akira S. (2007) TLR signaling. Semin. Immunol. 19:24-32.
22. Kawai T, Akira S. (2006) TLR signaling. Cell Death Differ. 13:816-25.
23. Lee MS, Kim YJ. (2007) Signaling pathways downstream of pattern-recognition receptors and their cross talk. Ann. Rev. Biochem. 76:447-80.
24. Matzinger P. (1994) Tolerance, danger, and the extended family. Ann. Rev. Immunol. 12:991-1045.
25. Bianchi ME. (2007) DAMPs, PAMPs and alarmins: all we need to know about danger. J. Leukoc. Biol. 81:1-5.
26. Miyake K. (2007) Innate immune sensing of pathogens and danger signals by cell surface Toll-like receptors. Semin. Immunol. 19:3-10.
27. Neal MD, et al. (2006) Enterocyte TLR4 mediates phagocytosis and translocation of bacteria across the intestinal barrier. J. Immunol. 176:3070-9.
28. Noulin N, et al. (2005) Both hemopoietic and resident cells are required for MyD88-dependent pulmonary inflammatory response to inhaled endotoxin. J. Immunol. 175:6861-9.
29. Hajjar AM, et al. (2005) An essential role for nonbone marrow-derived cells in control of Pseudomonas aeruginosa pneumonia. Am. J. Respir. Cell. Mol. Biol. 33:470-5.
30. Schilling JD, Martin SM, Hung CS, Lorenz RG, Hultgren SJ. (2003) Toll-like receptor 4 on stromal and hematopoietic cells mediates innate resistance to uropathogenic Escherichia coli. Proc. Natl. Acad. Sci. U. S. A. 100:4203-8.
31. Zhang B, Ramesh G, Uematsu S, Akira S, Reeves WB. (2008) TLR4 signaling mediates inflammation and tissue injury in nephrotoxicity. J. Am. Soc. Nephrol. 19:923-32.
32. Leaphart CL, et al. (2007) A critical role for TLR4 in the pathogenesis of necrotizing enterocolitis by modulating intestinal injury and repair. J. Immunol. 179:4808-20.
33. Jilling T, et al. (2006) The roles of bacteria and TLR4 in rat and murine models of necrotizing enterocolitis. J. Immunol. 177:3273-82.
34. Phipps S, Lam CE, Foster PS, Matthaei KI. (2007) The contribution of toll-like receptors to the pathogenesis of asthma. Immunol. Cell Biol. 85:463-70.
35. Akira S, Takeda K. (2004) Toll-like receptor signalling. Nat. Rev. Immunol. 4:499-511.
36. Medzhitov R, Preston-Hurlburt P, Janeway CA Jr. (1997) A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388:394-7.
37. Hoshino K, et al. (1999) Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J. Immunol. 162:3749-52.
38. Kawai T, Adachi O, Ogawa T, Takeda K, Akira S. (1999) Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 11:115-22.
39. Theiner G, et al. (2008) TLR9 cooperates with TLR4 to increase IL-12 release by murine dendritic cells. Mol. Immunol. 45:244-52
40. Pestka S, Krause CD, Walter MR. (2004) Interferons, interferon-like cytokines, and their receptors. Immunol. Rev. 202:8-32.
41. Kawai T, et al. (2001) Lipopolysaccharide stimulates the MyD88-independent pathway and results in activation of IFN-regulatory factor 3 and the expression of a subset of lipopolysaccharide-inducible genes. J. Immunol. 167:5887-94.
42. Horng T, Barton GM, Medzhitov R. (2001) TIRAP: an adapter molecule in the Toll signaling pathway. Nat. Immunol. 2:835-41.
43. Fitzgerald KA, et al. (2001) Mal (MyD88-adapterlike) is required for Toll-like receptor-4 signal transduction. Nature 413:78-83.
44. Burns K, et al. (1998) MyD88, an adapter protein involved in interleukin-1 signaling. J. Biol. Chem. 273:12203-9.
45. Muzio M, Natoli G, Saccani S, Levrero M, Mantovani A. (1998) The human toll signaling pathway: divergence of nuclear factor kappaB and JNK/SAPK activation upstream of tumor necrosis factor receptor-associated factor 6 (TRAF6). J. Exp. Med. 187:2097-101.
46. Wesche H, Henzel WJ, Shillinglaw W, Li S, Cao Z. (1997) MyD88: an adapter that recruits IRAK to the IL-1 receptor complex. Immunity 7:837-47.
47. Cao Z, Xiong J, Takeuchi M, Kurama T, Goeddel DV. (1996) TRAF6 is a signal transducer for interleukin-1. Nature 383:443-6.
48. Deng L, et al. (2000) Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell 103:351-61.
49. Shibuya H, et al. (1996) TAB1: an activator of the TAK1 MAPKKK in TGF-beta signal transduction. Science 272:1179-82.
50. Takaesu G, et al. (2000) TAB2, a novel adaptor protein, mediates activation of TAK1 MAPKKK by linking TAK1 to TRAF6 in the IL-1 signal transduction pathway. Mol. Cell. 5:649-58.
51. Ishitani T, et al. (2003) Role of the TAB2-related protein TAB3 in IL-1 and TNF signaling. EMBO J. 22:6277-88.
52. Wang Q, Wang X, Hernandez A, Kim S, Evers B. (2001) Inhibition of the phosphatidylinositol 3-kinase pathway contributes to HT29 and Caco-2 intestinal cell differentiation. Gastroenterology 120:1381-92.
53. Shirakabe K, et al. (1997) TAK1 mediates the ceramide signaling to stress-activated protein kinase/c-Jun N-terminal kinase. J. Biol. Chem. 272:8141-4.
54. Moriguchi T, et al. (1996) A novel kinase cascade mediated by mitogen-activated protein kinase kinase 6 and MKK3. J. Biol. Chem. 271:13675-9.
55. An H, et al. (2002) Involvement of ERK, p38 and NF-kappaB signal transduction in regulation of TLR2, TLR4 and TLR9 gene expression induced by lipopolysaccharide in mouse dendritic cells. Immunology 106:38-45.
56. Morse D, et al. (2003) Suppression of inflammatory cytokine production by carbon monoxide involves the JNK pathway and AP-1. J. Biol. Chem. 278:36993-8.
57. Zhang Y, et al. (2001) The regulatory effect of ERK1/2 signal pathway on production of TNFalpha induced by LPS in mice Kupffer cells. Chin. J. Traumatol. 4:139-42.
58. Hayashi F, et al. (2001) The innate immune response to bacterial flagellin is mediated by Tolllike receptor 5. Nature 410:1099-103.
59. Hemmi H, et al. (2002) Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat. Immunol. 3:196-200.
60. Hacker H, et al. (2000) Immune cell activation by bacterial CpG-DNA through myeloid differentiation marker 88 and tumor necrosis factor receptor-associated factor (TRAF) 6. J. Exp. Med. 192:595-600.
61. Schnare M, Holt AC, Takeda K, Akira S, Medzhitov R. (2000) Recognition of CpG DNA is mediated by signaling pathways dependent on the adaptor protein MyD88. Curr. Biol. 10:1139-42.
62. Yamamoto M, et al. (2003) Role of adaptor TRIF in the MyD88-independent Toll-like receptor signaling pathway. Science 301:640-3.
63. Hoebe K, et al. (2003) Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature 424:743-8.
64. Sharma S, et al. (2003) Triggering the interferon antiviral response through an IKK-related pathway. Science 300:1148-51.
65. Fitzgerald KA, et al. (2003) IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nat. Immunol. 4:491-6.
66. Nakaya T, et al. (2001) Gene induction pathways mediated by distinct IRFs during viral infection. Biochem. Biophys. Res. Commun. 283:1150-6.
67. Sato S, et al. (2003) Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF) associates with TNF receptor-associated factor 6 and TANK-binding kinase 1, and activates two distinct transcription factors, NF-kappa B and IFN-regulatory factor-3, in the Toll-like receptor signaling. J. Immunol. 171:4304-10.
68. Meylan E, et al. (2004) RIP1 is an essential mediator of Toll-like receptor 3-induced NF-kappa B activation. Nat. Immunol. 5:503-7.
69. Caplan MS, Kelly A, Hsueh W. (1992) Endotoxin and hypoxia-induced intestinal necrosis in rats: the role of platelet activating factor. Pediatr. Res. 31:428-34.
70. De Plaen IG, et al. (2002) Endotoxin, but not platelet-activating factor, activates nuclear factor-kappaB and increases IkappaBalpha and IkappaBbeta turnover in enterocytes. Immunology 106:577-83.
71. Anand RJ, Leaphart CL, Mollen KP, Hackam DJ. (2007) The role of the intestinal barrier in the pathogenesis of necrotizing enterocolitis. Shock 27:124-33.
72. Gardiner KR, et al. (1995) Significance of systemic endotoxaemia in inflammatory bowel disease. Gut 36:897-901.
73. Ruemmele FM, et al. (2002) Lipopolysaccharide modulation of normal enterocyte turnover by toll-like receptors is mediated by endogenously produced tumour necrosis factor alpha. Gut 51:842-8.
74. Otte J, Cario E, Podolsky D. (2004) Mechanisms of cross hyporesponsiveness to Toll-like receptor bacterial ligands in intestinal epithelial cells. Gastroenterology 126:1054-70.
75. Cario E, Podolsky DK. (2000) Differential alteration in intestinal epithelial cell expression of toll-like receptor 3 (TLR3) and TLR4 in inflammatory bowel disease. Infect. Immun. 68:7010-7.
76. Funda DP, et al. (2001) CD14 Is Expressed and Released as Soluble CD14 by Human Intestinal Epithelial Cells In Vitro: Lipopolysaccharide Activation of Epithelial Cells Revisited. Infect. Immun. 69:3772-81.
77. Cario E, et al. (2002) Commensal-associated molecular patterns induce selective toll-like receptor-trafficking from apical membrane to cytoplasmic compartments in polarized intestinal epithelium. Am. J. Pathol. 160:165-73.
78. Szebeni B, et al. (2008) Increased expression of Toll-like receptor (TLR) 2 and TLR4 in the colonic mucosa of children with inflammatory bowel disease. Clin. Exp. Immunol. 151:34-41.
79. Gomariz RP, et al. (2005) Time-course expression of Toll-like receptors 2 and 4 in inflammatory bowel disease and homeostatic effect of VIP. J. Leukoc. Biol. 78:491-502.
80. Ortega-Cava CF, et al. (2003) Strategic compartmentalization of Toll-like receptor 4 in the mouse gut. J. Immunol. 170:3977-85.
81. Szebeni B, et al. (2007) Increased mucosal expression of Toll-like receptor (TLR)2 and TLR4 in coeliac disease. J. Pediatr. Gastroenterol. Nutr. 45:187-93.
82. Minino AM, Heron MP, Murphy SL, Kochanek KD. (2007) Deaths: final data for 2004. Natl. Vital Stat. Rep. 55:1-119.
83. Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R. (2004) Recognition of commensal microflora by Toll-like receptors is required for intestinal homeostasis. Cell 118:229-41.
84. Araki A, et al. (2005) MyD88-deficient mice develop severe intestinal inflammation in dextran sodium sulfate colitis. J. Gastroenterol. 40:16-23.
85. Fukata M, et al. (2005) Toll-like receptor-4 is required for intestinal response to epithelial injury and limiting bacterial translocation in a murine model of acute colitis. Am. J. Physiol. Gastrointest. Liver Physiol. 288:G1055-65.
86. Rakoff-Nahoum S, Hao L, Medzhitov R. (2006) Role of toll-like receptors in spontaneous commensal-dependent colitis. Immunity 25:319-29.
87. Kosloske AM, Musemeche CA. (1989) Necrotizing enterocolitis of the neonate. Clin. Perinatol. 16:97-111.
88. Abreu MT, et al. (2001) Decreased expression of Toll-like receptor-4 and MD-2 correlates with intestinal epithelial cell protection against dysregulated proinflammatory gene expression in response to bacterial lipopolysaccharide. J. Immunol. 167:1609-16.
89. Suzuki M, Hisamatsu T, Podolsky DK. (2003) Gamma interferon augments the intracellular pathway for lipopolysaccharide (LPS) recognition in human intestinal epithelial cells through coordinated up-regulation of LPS uptake and expression of the intracellular Toll-like receptor 4-MD-2 complex. Infect. Immun. 71:3503-11.
90. Cario E, Gerken G, Podolsky DK. (2007) Toll-Like receptor 2 controls mucosal inflammation by regulating epithelial barrier function. Gastroenterology 132:1359-74.
91. Lee J, et al. (2006) Maintenance of colonic homeostasis by distinctive apical TLR9 signalling in intestinal epithelial cells. Nat. Cell Biol. 8:1327-36.
92. Vijay-Kumar M, et al. (2007) Deletion of TLR5 results in spontaneous colitis in mice. J. Clin. Invest. 117:3909-21.
93. Vijay-Kumar M, et al. (2006) Flagellin suppresses epithelial apoptosis and limits disease during enteric infection. Am. J. Pathol. 169:1686-700.
94. Vijay-Kumar M, et al. (2007) Activation of toll-like receptor 3 protects against DSS-induced acute colitis. Inflamm. Bowel Dis. 13:856-64.
95. Ortega-Cava CF, et al. (2003) Strategic compartmentalization of Toll-like Receptor 4 in the mouse gut. J. Immunol. 170:3977-85.
96. Chaudhuri N, Whyte MK, Sabroe I. (2007) Reducing the toll of inflammatory lung disease. Chest 131:1550-6.
97. Saito T, Yamamoto T, Kazawa T, Gejyo H, Naito M. (2005) Expression of toll-like receptor 2 and 4 in lipopolysaccharide-induced lung injury in mouse. Cell Tissue Res. 321:75-88.
98. Berndt A, et al. (2007) Elevated amount of Tolllike receptor 4 mRNA in bronchial epithelial cells is associated with airway inflammation in horses with recurrent airway obstruction. Am. J. Physiol. Lung Cell Mol. Physiol. 292:L936-43.
99. Schmeck B, et al. (2006) Pneumococci induced TLR- and Rac1-dependent NF-kappaB-recruitment to the IL-8 promoter in lung epithelial cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 290: L730-7.
100. Armstrong L, et al. (2004) Expression of functional toll-like receptor-2 and -4 on alveolar epithelial cells. Am. J. Respir. Cell. Mol. Biol. 31:241-5.
101. Parilla NW, Hughes VS, Lierl KM, Wong HR, Page K. (2006) CpG DNA modulates interleukin 1beta-induced interleukin-8 expression in human bronchial epithelial (16HBE14o-) cells. Resp. Res. 7:84.
102. Schurr JR, et al. (2005) Central role of toll-like receptor 4 signaling and host defense in experimental pneumonia caused by Gram-negative bacteria. Infect. Immun. 73:532-45.
103. Wang X, et al. (2002) Toll-like receptor 4 mediates innate immune responses to Haemophilus influenzae infection in mouse lung. J. Immunol. 168:810-5.
104. Lee JS, et al. (2005) TLR-4 pathway mediates the inflammatory response but not bacterial elimination in E. coli pneumonia. Am. J. Physiol. Lung Cell Mol. Physiol. 289: L731-8.
105. Rodriguez N, et al. (2006) Differential involvement of TLR2 and TLR4 in host survival during pulmonary infection with Chlamydia pneumoniae. Eur. J. Immunol. 36:1145-55.
106. Kurt-Jones EA, et al. (2000) Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus. Nat. Immunol. 1:398-401.
107. Knapp S, et al. (2004) Toll-like receptor 2 plays a role in the early inflammatory response to murine pneumococcal pneumonia but does not contribute to antibacterial defense. J. Immunol. 172:3132-8.
108. Le Goffic R, et al. (2006) Detrimental contribution of the Toll-like receptor (TLR)3 to influenza A virus-induced acute pneumonia. PLoS Pathog. 2:e53.
109. Chassin C, et al. (2006) Renal collecting duct epithelial cells react to pyelonephritis-associated Escherichia coli by activating distinct TLR4-dependent and -independent inflammatory pathways. J. Immunol. 177:4773-84.
110. Tsuboi N, et al. (2002) Roles of toll-like receptors in C-C chemokine production by renal tubular epithelial cells. J. Immunol. 169:2026-33.
111. El-Achkar TM, et al. (2006) Sepsis induces changes in the expression and distribution of Toll-like receptor 4 in the rat kidney. Am. J. Physiol. Renal. Physiol. 290: F1034-43.
112. Wolfs TG, et al. (2002) In vivo expression of Toll-like receptor 2 and 4 by renal epithelial cells: IFN-gamma and TNF-alpha mediated up-regulation during inflammation. J. Immunol. 168:1286-93.
113. Cunningham PN, Wang Y, Guo R, He G, Quigg RJ. (2004) Role of Toll-like receptor 4 in endotoxin-induced acute renal failure. J. Immunol. 172:2629-35.
114. Zhang D, et al. (2004) A toll-like receptor that prevents infection by uropathogenic bacteria. Science 303:1522-6.
115. Leemans JC, et al. (2005) Renal-associated TLR2 mediates ischemia/reperfusion injury in the kidney. J. Clin. Invest. 115:2894-903.
116. Cluff CW, et al. (2005) Synthetic toll-like receptor 4 agonists stimulate innate resistance to infectious challenge. Infect. Immun. 73:3044-52.
117. Fort MM , et al. (2005) A synthetic TLR4 antagonist has anti-inflammatory effects in two murine models of inflammatory bowel disease. J. Immunol. 174:6416-23.
118. Brandl K, Gluck T, Hartmann P, Salzberger B, Falk W. (2005) A designed TLR4/MD-2 complex to capture LPS. J. Endotoxin Res. 11:197-206.
119. Iwami KI, et al. (2000) Cutting edge: naturally occurring soluble form of mouse Toll-like receptor 4 inhibits lipopolysaccharide signaling. J. Immunol. 165:6682-6686.
120. Loiarro M, et al. (2007) Pivotal Advance: Inhibition of MyD88 dimerization and recruitment of IRAK1 and IRAK4 by a novel peptidomimetic compound. J. Leukoc. Biol. 82:801-10.
121. Ii M, et al. (2006) A novel cyclohexene derivative, ethyl (6R)-6-[N- (2-Chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate (TAK-242), selectively inhibits toll-like receptor 4-mediated cytokine production through suppression of intracellular signaling. Mol. Pharmacol. 69:1288-95.
122. Yamada M, et al. (2005) Discovery of novel and potent small-molecule inhibitors of NO and cytokine production as antisepsis agents: synthesis and biological activity of alkyl 6- (N-substituted sulfamoyl) cyclohex-1-ene-1-carboxylate. J. Med. Chem. 48:7457-67.
123. Harte MT, et al. (2003) The poxvirus protein A52R targets Toll-like receptor signaling complexes to suppress host defense. J. Exp. Med. 197:343-51.
124. McCoy SL, Kurtz SE, Macarthur CJ, Trune DR, Hefeneider SH. (2005) Identification of a peptide derived from vaccinia virus A52R protein that inhibits cytokine secretion in response to TLR-dependent signaling and reduces in vivo bacterial-induced inflammation. J. Immunol. 174:3006-14.
125. Tsung A, et al. (2007) A novel inhibitory peptide of Toll-like receptor signaling limits lipopolysaccharide-induced production of inflammatory mediators and enhances survival in mice. Shock 27:364-9.
126. Takeuchi O, et al. (2002) Cutting edge: role of Toll-like receptor 1 in mediating immune response to microbial lipoproteins. J. Immunol. 169:10-14.
127. Aliprantis AO, et al. (1999) Cell activation and apoptosis by bacterial lipoproteins through tolllike receptor-2. Science 285:736-9.
128. Schwandner R, Dziarski R, Wesche H, Rothe M, Kirschning CJ. (1999) Peptidoglycan- and lipoteichoic acid-induced cell activation is mediated by toll-like receptor 2. J. Biol. Chem. 274:17406-9.
129. Takeuchi O, et al. (1999) Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components. Immunity. 11:443-51.
130. Underhill DM, et al. (1999) The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens. Nature 401:811-5.
131. Ozinsky A, et al. (2000) The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between Toll-like receptors. Proc. Natl. Acad. Sci. U. S. A. 97:13766-71.
132. Vabulas RM, et al. (2002) HSP70 as endogenous stimulus of the Toll/interleukin-1 receptor signal pathway. J. Biol. Chem. 277:15107-12.
133. Asea A, et al. (2002) Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4. J. Biol. Chem. 277:15028-34.
134. Alexopoulou L, Holt AC, Medzhitov R, Flavell RA. (2001) Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 413:732-8.
135. Poltorak A, et al. (1998) Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282:2085-8.
136. Kawasaki K, et al. (2000) Mouse toll-like receptor 4.MD-2 complex mediates lipopolysaccharide-mimetic signal transduction by Taxol. J. Biol. Chem. 275:2251-4.
137. Bulut Y, et al. (2002) Chlamydial heat shock protein 60 activates macrophages and endothelial cells through Toll-like receptor 4 and MD2 in a MyD88-dependent pathway. J. Immunol. 168:1435-40.
138. Ohashi K, Burkart V, Flohe S, Kolb H. (2000) Cutting edge: heat shock protein 60 is a putative endogenous ligand of the toll-like receptor-4 complex. J. Immunol. 164:558-61.
139. Okamura Y, et al. (2001) The extra domain A of fibronectin activates Toll-like receptor 4. J. Biol. Chem. 276:10229-33.
140. Termeer C, et al. (2002) Oligosaccharides of Hyaluronan activate dendritic cells via toll-like receptor 4. J. Exp. Med. 195:99-111.
141. Johnson GB, Brunn GJ, Kodaira Y, Platt JL. (2002) Receptor-mediated monitoring of tissue well-being via detection of soluble heparan sulfate by Toll-like receptor 4. J. Immunol. 168:5233-9.
142. Smiley ST, King JA, Hancock WW. (2001) Fibrinogen stimulates macrophage chemokine secretion through toll-like receptor 4. J. Immunol. 167:2887-94.
143. Rassa JC, Meyers JL, Zhang Y, Kudaravalli R, Ross SR. (2002) Murine retroviruses activate B cells via interaction with toll-like receptor 4. Proc. Natl. Acad. Sci. U. S. A. 99:2281-6.
144. Takeuchi O, et al. (2001) Discrimination of bacterial lipoproteins by Toll-like receptor 6. Int. Immunol. 13:933-40.
145. Diebold SS, Kaisho T, Hemmi H, Akira S, Reis e Sousa C. (2004) Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303:1529-31.
146. Heil F, et al. (2004) Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 303:1526-9.
147. Jurk M, et al. (2006) Modulating responsiveness of human TLR7 and 8 to small molecule ligands with T-rich phosphorothiate oligodeoxynucleotides. Eur. J. Immunol. 36:1815-26.
148. Hemmi H, et al. (2000) A Toll-like receptor recognizes bacterial DNA. Nature 408:740-5.
149. Yarovinsky F, et al. (2005) TLR11 activation of dendritic cells by a protozoan profilin-like protein. Science 308:1626-9.
150. Guillot L, et al. (2002) Cutting edge: the immunostimulatory activity of the lung surfactant protein-A involves Toll-like receptor 4. J. Immunol. 168:5989-92.
151. Biragyn A, et al. (2002) Toll-like receptor 4-dependent activation of dendritic cells by beta-defensin 2. Science 298:1025-9.
152. Hoshino K, et al. (1999) Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J. Immunol. 162:3749-52.
153. Park JS, et al. (2004) Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J. Biol. Chem. 279:7370-7.
154. Kariko K, Ni H, Capodici J, Lamphier M, Weissman D. (2004) mRNA is an endogenous ligand for Toll-like receptor 3. J. Biol. Chem. 279:12542-50.
155. Ishii KJ, et al. (2001) Genomic DNA released by dying cells induces the maturation of APCs. J. Immunol. 167:2602-7.
156. Shi Y, Evans JE, Rock KL. (2003) Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 425:516-21.
157. Rock FL, Hardiman G, Timans JC, Kastelein RA, Bazan JF. (1998) A family of human receptors structurally related to Drosophila Toll. Proc. Natl. Acad. Sci. U. S. A. 95:588-93.
158. Otte JM, Cario E, Podolsky DK. (2004) Mechanisms of cross hyporesponsiveness to Toll-like receptor bacterial ligands in intestinal epithelial cells. Gastroenterology 126:1054-70.
159. Melmed G, et al. (2003) Human intestinal epithelial cells are broadly unresponsive to Tolllike receptor 2-dependent bacterial ligands: implications for host-microbial interactions in the gut J. Immunol. 170:1406-15.
160. Muir A, et al. (2004) Toll-like receptors in normal and cystic fibrosis airway epithelial cells. Am. J. Respir. Cell. Mol. Biol. 30:777-83.
161. Becker MN, Diamond G, Verghese MW, Randell SH. (2000) CD14-dependent lipopolysaccharide-induced beta-defensin-2 expression in human tracheobronchial epithelium. J. Biol. Chem. 275:29731-6.
162. Greene CM, et al. (2005) TLR-induced inflammation in cystic fibrosis and non-cystic fibrosis airway epithelial cells. J. Immunol. 174:1638-46.
163. Zhang Z, Louboutin JP, Weiner DJ, Goldberg JB, Wilson JM. (2005) Human airway epithelial cells sense Pseudomonas aeruginosa infection via recognition of flagellin by Toll-like receptor 5. Infect. Immun. 73:7151-60.
164. Naik S, Kelly EJ, Meijer L, Pettersson S, Sanderson IR. (2001) Absence of Toll-like receptor 4 explains endotoxin hyporesponsiveness in human intestinal epithelium. J. Pediatr. Gastroenterol. Nutr. 32:449-53.
165. Cario E, et al. (2000) Lipopolysaccharide activates distinct signaling pathways in intestinal epithelial cell lines expressing Toll-like receptors. J. Immunol. 164:966-72.
166. Ortega-Cava CF, et al. (2006) Epithelial toll-like receptor 5 is constitutively localized in the mouse cecum and exhibits distinctive downregulation during experimental colitis. Clin. Vaccine Immunol. 13:132-8.
167. Droemann D, et al. (2003) Toll-like receptor 2 is expressed by alveolar epithelial cells type II and macrophages in the human lung. Histochem. Cell Biol. 119:103-8.
168. Hauber HP, et al. (2005) Toll-like receptors 4 and 2 expression in the bronchial mucosa of patients with cystic fibrosis. Can. Respir. J. 12:13-8.
169. Adamo R, Sokol S, Soong G, Gomez MI, Prince A. (2004) Pseudomonas aeruginosa flagella activate airway epithelial cells through asialoGM1 and toll-like receptor 2 as well as toll-like receptor 5. Am. J. Respir. Cell. Mol. Biol. 30:627-34.
170. Shigeoka AA, et al. (2007) TLR2 is constitutively expressed within the kidney and participates in ischemic renal injury through both MyD88-dependent and -independent pathways. J. Immunol. 178:6252-8.
171. Backhed F, Soderhall M, Ekman P, Normark S, Richter-Dahlfors A. (2001) Induction of innate immune responses by Escherichia coli and purified lipopolysaccharide correlate with organand cell-specific expression of Toll-like receptors within the human urinary tract. Cell. Microbiol. 3:153-8.
172. Groskreutz DJ, et al. (2006) Respiratory syncytial virus induces TLR3 protein and protein kinase R, leading to increased double-stranded RNA responsiveness in airway epithelial cells. J. Immunol. 176:1733-40.
173. Bambou JC, et al. (2004) In vitro and ex vivo activation of the TLR5 signaling pathway in intestinal epithelial cells by a commensal Escherichia coli strain. J. Biol. Chem. 279:42984-92.
174. Hornef MW, Frisan T, Vandewalle A, Normark S, Richter-Dahlfors A. (2002) Toll-like receptor 4 resides in the Golgi apparatus and colocalizes with internalized lipopolysaccharide in intestinal epithelial cells. J. Exp. Med. 195:559-70.
175. Guillot L, et al. (2004) Response of human pulmonary epithelial cells to lipopolysaccharide involves Toll-like receptor 4 (TLR4)-dependent signaling pathways: evidence for an intracellular compartmentalization of TLR4. J. Biol. Chem. 279:2712-8.
176. Samuelsson P, Hang L, Wullt B, Irjala H, Svanborg C. (2004) Toll-like receptor 4 expression and cytokine responses in the human urinary tract mucosa. Infect. Immun. 72:3179-86.
177. Du X, Poltorak A, Wei Y, Beutler B. (2000) Three novel mammalian toll-like receptors: gene structure, expression, and evolution. Eur. Cytokine Netw. 11:362-71.
178. Pawar RD, et al. (2006) Toll-like receptor-7 modulates immune complex glomerulonephritis. J. Am. Soc. Nephrol. 17:141-9.
179. Droemann D, et al. (2005) Human lung cancer cells express functionally active Toll-like receptor 9. Respir. Res. 6:1.
180. Anders HJ, Schlondorff D. (2007) Toll-like receptors: emerging concepts in kidney disease. Curr. Opin. Nephrol. Hypertens. 16:177-83.
181. Rumio C, et al. (2004) Degranulation of paneth cells via toll-like receptor 9. Am. J. Pathol. 165:373-81.
182. Ewaschuk JB, et al. (2007) Surface expression of Toll-like receptor 9 is upregulated on intestinal epithelial cells in response to pathogenic bacterial DNA. Infect. Immun. 75:2572-9.
183. Pedersen G, Andresen L, Matthiessen MW, Rask-Madsen J, Brynskov J. (2005) Expression of Toll-like receptor 9 and response to bacterial CpG oligodeoxynucleotides in human intestinal epithelium. Clin. Exp. Immunol. 141:298-306.
184. Anders HJ, et al. (2004) Activation of toll-like receptor-9 induces progression of renal disease in MRL-Fas (lpr) mice. FASEB J. 18:534-6.
185. Chuang T, Ulevitch RJ. (2001) Identification of hTLR10: a novel human Toll-like receptor preferentially expressed in immune cells. Biochim. Biophys. Acta. 1518:157-61.
186. Cambi A, Figdor CG. (2005). Levels of complexity in pathogen recognition by C-type lectins. Curr. Opin. Immunol. 17:345-51.
187. Arbour NC, et al. (2000) TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat. Genet. 25:187-91.
188. Hawn TR, et al. (2005). Toll-like receptor 4 polymorphisms are associated with resistance to Legionnaires' disease. Proc. Natl. Acad. Sci. U. S. A. 102:2487-9.
189. Palmer SM, et al. (2006). Donor polymorphisms in Toll-like receptor-4 influence the development of rejection after renal transplantation. Clin. Transplant. 20:30-6.
190. Nogueira E, et al. (2007). Incidence of donor and recipient toll-like receptor-4 polymorphisms in kidney transplantation. Transplant. Proc. 39:412-4.
191. Lenoir C, et al. (2008). MD-2 controls bacterial lipopolysaccharide hyporesponsiveness in human intestinal epithelial cells. Life Sci. 82:519-28.
192. Abreu MT, et al. (2002). TLR4 and MD-2 expression is regulated by immune-mediated signals in human intestinal epithelial cells. J. Biol. Chem. 277:20431-7.
193. Mollen, KP, et al. (2008) Increased expression and internalization of the endotoxin coreceptor CD14 in enterocytes occur as an early event in the development of experimental necrotizing enterocolitis. J. Pediatr. Surg. 43:1175-81.
194. Mayer AK, et al. (2007). Differential recognition of TLR-dependent microbial ligands in human bronchial epithelial cells. J. Immunol. 178:3134-42.
195. Hornef MW, Normark BH, Vandewalle A, Normark S. (2003). Intracellular recognition of lipopolysaccharide by toll-like receptor 4 in intestinal epithelial cells. J. Exp. Med. 198:1225-35.
196. Ewaschuk JB, et al. (2007) Surface expression of Toll-like receptor 9 is upregulated on intestinal epithelial cells in response to pathogenic bacterial DNA. Infect. Immun. 75:2572-9.
197. Muir A, et al. (2004). Toll-like receptors in normal and cystic fibrosis airway epithelial cells. Am. J. Respir. Cell Mol. Biol. 30:777-83.
198. Lotz M, et al. (2006). Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells. J. Exp. Med. 203:973-84.
199. Shibolet O, Podolsky DK. (2007) TLRs in the Gut. IV. Negative regulation of Toll-like receptors and intestinal homeostasis: addition by subtraction. Am. J. Physiol. Gastrointest. Liver Physiol. 292:G1469-73.