Functional consequences of NOD2 (CARD15) mutations

Inflammatory Bowel Diseases

Volumn 12, Issue 7, 2006, Pages 641-650

  Abraham, Clara ^a   Cho, Judy H ^a  

^a UNIVERSITY OF CHICAGO   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CASPASE RECRUITMENT DOMAIN PROTEIN 15; CYTOKINE; DEFENSIN; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; PEPTIDOGLYCAN; TOLL LIKE RECEPTOR;

ANTIMICROBIAL ACTIVITY; BLAU SYNDROME; COMMENSALISM; CROHN DISEASE; CYTOKINE RELEASE; GENE MUTATION; GRAFT VERSUS HOST REACTION; HOST RESISTANCE; HUMAN; IMMUNITY; IMMUNOLOGICAL TOLERANCE; INFLAMMATION; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; REVIEW; SIGNAL TRANSDUCTION;

ANIMALS; ANTI-INFECTIVE AGENTS; CROHN DISEASE; CYTOKINES; DEFENSINS; HUMANS; INFLAMMATION; INTESTINES; MODELS, BIOLOGICAL; MODELS, GENETIC; MUTATION; NOD2 SIGNALING ADAPTOR PROTEIN; SIGNAL TRANSDUCTION;

EID: 33745536739     PISSN: 10780998     EISSN: 15364844     Source Type: Journal    
DOI: 10.1097/01.MIB.0000225332.83861.5f     Document Type: Review

References (114)

1. Ogura Y, Bonen DK, Inohara N, et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature. 2001;411:603-606.
2. Hugot JP, Chamaillard M, Zouali H, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature. 2001;411:599-603.
3. Holler E, Rogler G, Brenmoehl J, et al. Prognostic significance of NOD2/CARD15 variants in HLA-identical sibling hematopoietic stem cell transplantation: effect on long term outcome is confirmed in 2 independent cohorts and may be modulated by the type of gastrointestinal decontamination. Blood. 2006;107:4189-4193.
4. Holler E, Rogler G, Herfarth H, et al. Both donor and recipient NOD2/CARD15 mutations associate with transplant-related mortality and GvHD following allogeneic stem cell transplantation. Blood. 2004;104:889-894.
5. Miceli-Richard C, Lesage S, Rybojad M, et al. CARD15 mutations in Blau syndrome. Nat Genet. 2001;29:19-20.
6. Inohara N, Ogura Y, Fontalba A, et al. Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease. J Biol Chem. 2003;278:5509-5512.
7. Girardin SE, Boneca IG, Viala J, et al. Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem. 2003;278:8869-8872.
8. Ogura Y, Inohara N, Benito A. Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB. J Biol Chem. 2001;276:4812-4818.
9. Tanabe T, Chamaillard M, Ogura Y, et al. Regulatory regions and critical residues of NOD2 involved in muramyl dipeptide recognition. EMBO J. 2004;23:1587-1597.
10. Li J, Moran T, Swanson E, et al. Regulation of IL-8 and IL-1beta expression in Crohn's disease associated NOD2/CARD15 mutations. Hum Mol Genet. 2004;13:1715-1725.
11. Netea MG, Kullberg BJ, de Jong DJ, et al. NOD2 mediates anti-inflammatory signals induced by TLR2 ligands: implications for Crohn's disease. Eur J Immunol. 2004;34:2052-2059.
12. Economou M, Trikalinos TA, Loizou KT, et al. Differential effects of NOD2 variants on Crohn's disease risk and phenotype in diverse populations: a metaanalysis. Am J Gastroenterol. 2004;99:2393-2404.
13. Bonen DK, Ogura Y, Nicolae DL, et al. Crohn's disease-associated NOD2 variants share a signaling defect in response to lipopolysaccharide and peptidoglycan. Gastroenterology. 2003;124:140-146.
14. Chamaillard M, Philpott D, Girardin SE, et al. Gene-environment interaction modulated by allelic heterogeneity in inflammatory diseases. Proc Natl Acad Sci U S A. 2003;100:3455-3460.
15. Netea MG, Ferwerda G, de Jong DJ, et al. Nucleotide-binding oligomerization domain-2 modulates specific TLR pathways for the induction of cytokine release. J Immunol. 2005;174:6518-6523.
16. van Heel DA, Ghosh S, Butler M, et al. Muramyl dipeptide and toll-like receptor sensitivity in NOD2-associated Crohn's disease. Lancet. 2005;365:1794-1796.
17. van Heel DA, Ghosh S, Hunt KA, et al. Synergy between TLR9 and NOD2 innate immune responses is lost in genetic Crohn's disease. Gut. 2005;54:1553-1557.
18. Lesage S, Zouali H, Cezard JP, et al. CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease. Am J Hum Genet. 2002;70:845-857.
19. Tanabe T, Chamaillard M, Ogura Y, et al. Regulatory regions and critical residues of NOD2 involved in muramyl dipeptide recognition. EMBO J. 2004;23:1587-1597.
20. Schurmann M, Valentonyte R, Hampe J, et al. CARD15 gene mutations in sarcoidosis. Eur Respir J. 2003;22:748-754.
21. Ho LP, Merlin F, Gaber K, et al. CARD 15 gene mutations in sarcoidosis. Thorax. 2005;60:354-355.
22. Kanazawa N, Okafuji I, Kambe N, et al. Early-onset sarcoidosis and CARD15 mutations with constitutive nuclear factor-kappaB activation: common genetic etiology with Blau syndrome. Blood. 2005;105:1195-1197.
23. Rosenstiel P, Fantini M, Brautigam K, et al. TNF-alpha and IFN-gamma regulate the expression of the NOD2 (CARD15) gene in human intestinal epithelial cells. Gastroenterology. 2003;124:1001-1009.
24. Lala S, Ogura Y, Osborne C, et al. Crohn's disease and the NOD2 gene: a role for Paneth cells. Gastroenterology. 2003;125:47-57.
25. Hisamatsu T, Suzuki M, Reinecker HC, et al. CARD15/NOD2 functions as an antibacterial factor in human intestinal epithelial cells. Gastroenterology. 2003;124:993-1000.
26. Ogura Y, Lala S, Xin W, et al. Expression of NOD2 in Paneth cells: a possible link to Crohn's ileitis. Gut. 2003;52:1591-1597.
27. Otte JM, Rosenberg IM, Podolsky DK. Intestinal myofibroblasts in innate immune responses of the intestine. Gastroenterology. 2003;124:1866-1878.
28. Davey MP, Martin TM, Planck SR, et al. Human endothelial cells express NOD2/CARD15 and increase IL-6 secretion in response to muramyl dipeptide. Microvasc Res. 2006.
29. Gutierrez O, Pipaon C, Inohara N, et al. Induction of Nod2 in myelomonocytic and intestinal epithelial cells via nuclear factor-kappa B activation. J Biol Chem. 2002;277:41701-41705.
30. Yang S, Takahashi N, Yamashita T, et al. Muramyl dipeptide enhances osteoclast formation induced by lipopolysaccharide, IL-1α, and TNF-α through nucleotide-binding oligomerization domain 2-mediated signaling in osteoblasts. J Immunol. 2005;175:1956-1964.
31. Tada H, Aiba S, Shibata K, et al. Synergistic effect of Nod1 and Nod2 agonists with toll-like receptor agonists on human dendritic cells to generate interleukin-12 and T helper type 1 cells. Infect Immun. 2005;73:7967-7976.
32. Stockinger S, Reutterer B, Schaljo B, et al. IFN regulatory factor 3-dependent induction of type I IFNs by intracellular bacteria is mediated by a TLR- and Nod2-independent mechanism. J Immunol. 2004;173:7416-7425.
33. Berrebi D, Maudinas R, Hugot JP, et al. Card15 gene overexpression in mononuclear and epithelial cells of the inflamed Crohn's disease colon. Gut. 2003;52:840-846.
34. Barnich N, Aguirre JE, Reinecker HC, et al. Membrane recruitment of NOD2 in intestinal epithelial cells is essential for nuclear factor-κ activation in muramyl dipeptide recognition. J Cell Biol. 2005;170:21-26.
35. McDonald C, Chen FF, Ollendorff V, et al. A role for Erbin in the regulation of Nod2-dependent NF-kappaB signaling. J Biol Chem. 2005;280:40301-40309.
36. Travassos LH, Girardin SE, Philpott DJ, et al. Toll-like receptor 2-dependent bacterial sensing does not occur via peptidoglycan recognition. EMBO Rep. 2004;5:1000-1006.
37. Dziarski R, Gupta D. Staphylococcus aureus peptidoglycan is a toll-like receptor 2 activator: a reevaluation. Infect Immun. 2005;73:5212-5216.
38. Inohara, Chamaillard, McDonald C, et al. NOD-LRR proteins: role in host-microbial interactions and inflammatory disease. Annu Rev Biochem. 2005;74:355-383.
39. Chamaillard M, Hashimoto M, Horie Y, An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid. Nat Immunol. 2003;4:702-707.
40. Vavricka SR, Musch MW, Chang JE, et al. hPepT1 transports muramyl dipeptide, activating NF-kappaB and stimulating IL-8 secretion in human colonic Caco2/bbe cells. Gastroenterology. 2004;127:1401-1409.
41. Viala J, Sansonetti P, Philpott DJ. Nods and "intracellular" innate immunity. C R Biol. 2004;327:551-555.
42. Girardin SE, Boneca IG, Carneiro LA, et al. Nod1 detects a unique muropeptide from gram-negative bacterial peptidoglycan. Science. 2003;300:1584-1587.
43. Netea MG, Ferwerda G, de Jong DJ, et al. The frameshift mutation in Nod2 results in unresponsiveness not only to Nod2- but also Nod1-activating peptidoglycan agonists. J Biol Chem. 2005;280:35859-35867.
44. McGovern DP, Hysi P, Ahmad T, et al. Association between a complex insertion/deletion polymorphism in NOD1 (CARD4) and susceptibility to inflammatory bowel disease. Hum Mol Genet. 2005;14:1245-1250.
45. Weichart D, Gobom J, Klopfleisch S, et al. Analysis of NOD2-mediated proteome response to muramyl dipeptide in HEK293 cells. J Biol Chem. 2006;281:2380-2389.
46. Vidal V, Dewulf J, Bahr GM. Enhanced maturation and functional capacity of monocyte-derived immature dendritic cells by the synthetic immunomodulator Murabutide. Immunology. 2001;103:479-487.
47. Vidal VF, Casteran N, Riendeau CJ, et al. Macrophage stimulation with Murabutide, an HIV-suppressive muramyl peptide derivative, selectively activates extracellular signal-regulated kinases 1 and 2, C/EBPbeta and STAT1: role of CD14 and Toll-like receptors 2 and 4. Eur J Immunol. 2001;31:1962-1971.
48. Kobayashi KS, Chamaillard M, Ogura Y, et al. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science. 2005;307:731-734.
49. Damiano JS, Oliveira V, Welsh K, et al. Heterotypic interactions among NACHT domains: implications for regulation of innate immune responses. Biochem J. 2004;381:213-219.
50. Chen CM, Gong Y, Zhang M, et al. Reciprocal cross-talk between Nod2 and TAK1 signaling pathways. J Biol Chem. 2004;279:25876-25882.
51. Barnich N, Hisamatsu T, Aguirre JE, et al. GRIM-19 interacts with nucleotide oligomerization domain 2 and serves as downstream effector of anti-bacterial function in intestinal epithelial cells. J Biol Chem. 2005;280:19021-19026.
52. Opitz B, Puschel A, Schmeck B, et al. Nucleotide-binding oligomerization domain proteins are innate immune receptors for internalized Streptococcus pneumoniae. J Biol Chem. 2004;279:36426-36432.
53. Kobayashi K, Inohara N, Hernandez LD, et al. RICK/Rip2/CARDIAK mediates signalling for receptors of the innate and adaptive immune systems. Nature. 2002;416:194-199.
54. Watanabe T, Kitani A, Murray PJ, et al. NOD2 is a negative regulator of Toll-like receptor 2-mediated T helper type 1 responses. Nat Immunol. 2004;5:800-808.
55. Abbott DW, Wilkins A, Asara JM, et al. The Crohn's disease protein, NOD2, requires RIP2 in order to induce ubiquitinylation of a novel site on NEMO. Curr Biol. 2004;14:2217-2227.
56. Kramer M, Netea MG, de Jong DJ, et al. Impaired dendritic cell function in Crohn's disease patients with NOD2 3020insC mutation. J Leukoc Biol. 2006;79:860-866.
57. Dzierzbicka K, Kolodziejczyk AM, Wysocka-Skrzela B, et al. Synthesis and antitumor activity of conjugates of muramyldipeptide, normuramyldipeptide, and desmuramylpeptides with acridine/acridone derivatives. J Med Chem. 2001;44:3606-3615.
58. Traub S, Kubasch N, Morath S, et al. Structural requirements of synthetic muropeptides to synergize with lipopolysaccharide in cytokine induction. J Biol Chem. 2004;279:8694-8700.
59. Venkataprasad N. Evidence of differential mycobacterial growth and modulation of mycobactericidal property by glucoaminylmuramyl dipeptide in murine macrophages. Ann N Y Acad Sci. 1997;832:117-129.
60. Takada H, Kawabata Y, Kawata S, et al. Structural characteristics of peptidoglycan fragments required to prime mice for induction of anaphylactoid reactions by lipopolysaccharides. Infect Immun. 1996;64:657-659.
61. Cohen LY, Bahr GM, Darcissac EC, et al. Modulation of expression of class II MHC and CD40 molecules in murine B cells by various muramyl dipeptides. Cell Immunol. 1996;169:75-84.
62. Fritz JH, Girardin SE, Fitting C, et al. Synergistic stimulation of human monocytes and dendritic cells by Toll-like receptor 4 and NOD1- and NOD2-activating agonists. Eur J Immunol. 2005;35:2459-2470.
63. Iinuma H, Nerome K, Yoshioka Y, et al. Characteristics of cytotoxic T lymphocytes directed to influenza virus haemagglutinin elicited by immunization with muramyldipeptide-influenza liposome vaccine. Scand J Immunol. 1995;41:1-10.
64. Todate A, Suda T, Kuwata H, et al. Muramyl dipeptide-Lys stimulates the function of human dendritic cells. J Leukoc Biol. 2001;70:723-729.
65. Yang S, Tamai R, Akashi S, et al. Synergistic effect of muramyldipeptide with lipopolysaccharide or lipoteichoic acid to induce inflammatory cytokines in human monocytic cells in culture. Infect Immun. 2001;69:2045-2053.
66. Wolfert MA, Murray TF, Boons GJ, et al. The origin of the synergistic effect of muramyl dipeptide with endotoxin and peptidoglycan. J Biol Chem. 2002;277:39179-39186.
67. Netea MG, Azam T, Ferwerda G, et al. IL-32 synergizes with nucleotide oligomerization domain (NOD) 1 and NOD2 ligands for IL-1βand IL-6 production through a caspase 1-dependent mechanism. Proc Natl Acad Sci U S A. 2005;102:16309-16314.
68. Uehara A, Yang S, Fujimoto Y, et al. Muramyldipeptide and diaminopimelic acid-containing desmuramylpeptides in combination with chemically synthesized Toll-like receptor agonists synergistically induced production of interleukin-8 in a NOD2- and NOD1-dependent manner, respectively, in human monocytic cells in culture. Cell Microbiol. 2005;7:53-61.
69. van Heel DA, Ghosh S, Butler M, et al. Synergistic enhancement of Toll-like receptor responses by NOD1 activation. Eur J Immunol. 2005;2471-2476.
70. Ferwerda G, Girardin SE, Kullberg BJ, NOD2 and toll-like receptors are nonredundant recognition systems of Mycobacterium tuberculosis. PLoS Pathog. 2005;1:279-285.
71. Kalyuzhin OV, Kalina NG, Bashtanenko AF, Stimulation of mouse resistance to bacterial infection with muramyl dipeptide glycoside. Bull Exp Biol Med. 2003;135:452-455.
72. Mukherjee K, Parashuraman S, Krishnamurthy G, et al. Diverting intracellular trafficking of Salmonella to the lysosome through activation of the late endocytic Rab7 by intracellular delivery of muramyl dipeptide. J Cell Sci. 2002;115:3693-3701.
73. Ayabe T, Satchell DP, Wilson CL, et al. Secretion of microbicidal alpha-defensins by intestinal Paneth cells in response to bacteria. Nat Immunol. 2000;1:113-118.
74. Duits LA, Ravensbergen B, Rademaker M, et al. Expression of beta-defensin 1 and 2 mRNA by human monocytes, macrophages and dendritic cells. Immunology. 2002;106:517-525.
75. Pamer EG. Immune responses to Listeria monocytogenes. Nat Rev Immunol. 2004;4:812-823.
76. Viala J, Chaput C, Boneca IG, et al. Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island. Nat Immunol. 2004;5:1166-1174.
77. Kim JG, Lee SJ, Kagnoff MF. Nod1 is an essential signal transducer in intestinal epithelial cells infected with bacteria that avoid recognition by toll-like receptors. Infect Immun. 2004;72:1487-1495.
78. Takeuchi K, Maiden L, Bjarnason I. Genetic aspects of intestinal permeability in inflammatory bowel disease. Novartis Found Symp. 2004;263:151-163, 211-218.
79. Buhner S, Buning C, Genschel J, et al. Genetic basis for increased intestinal permeability in families with Crohn's disease: role of CARD15 3020insC mutation? Gut. 2006;342-347.
80. Fries W, Renda MC, Lo Presti MA, et al. Intestinal permeability and genetic determinants in patients, first-degree relatives, and controls in a high-incidence area of Crohn's disease in Southern Italy. Am J Gastroenterol. 2005;100:2730-2736.
81. Pauleau AL, Murray PJ. Role of nod2 in the response of macrophages to toll-like receptor agonists. Mol Cell Biol. 2003;23:7531-7539.
82. Owen RL. Uptake and transport of intestinal macromolecules and microorganisms by M cells in Peyer's patches - a personal and historical perspective. Semin Immunol. 1999;11:157-163.
83. Rescigno M, Urbano M, Valzasina B, et al. Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nat Immunol. 2001;2:361-367.
84. Erdman S, Fox JG, Dangler CA, et al. Typhlocolitis in NF-kappa B-deficient mice. J Immunol. 2001;166:1443-1447.
85. Tomczak MF, Erdman SE, Poutahidis T, et al. NF-kappa B is required within the innate immune system to inhibit microflora-induced colitis and expression of IL-12 p40. J Immunol. 2003;171:1484-1492.
86. Gadjeva M, Tomczak MF, Zhang M, et al. A role for NF-kappa B subunits p50 and p65 in the inhibition of lipopolysaccharide-induced shock. J Immunol. 2004;173:5786-5793.
87. Tomczak MF, Gadjeva M, Wang YY, et al. Defective activation of ERK in macrophages lacking the p50/p105 subunit of NF-kappaB is responsible for elevated expression of IL-12 p40 observed after challenge with Helicobacter hepaticus. J Immunol. 2006;176:1244-1251.
88. Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, et al. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell. 2004;118:229-241.
89. Maeda S, Hsu LC, Liu H, et al. Nod2 mutation in Crohn's disease potentiates NF-kappaB activity and IL-1beta processing. Science. 2005;307:734-738.
90. Netea MG, Ferwerda G, de Jong DJ, et al. NOD2 3020insC mutation and the pathogenesis of Crohn's disease: impaired IL-1beta production points to a loss-of-function phenotype. Neth J Med. 2005;63:305-308.
91. Eckmann L, Karin M. NOD2 and Crohn's disease: loss or gain of function? Immunity. 2005;22:661-667.
92. Wehkamp J, Harder J, Weichenthal M, et al. NOD2 (CARD15) mutations in Crohn's disease are associated with diminished mucosal alpha-defensin expression. Gut. 2004;53:1658-1664.
93. Wehkamp J, Salzman NH, Porter E, et al. Reduced Paneth cell alpha-defensins in ileal Crohn's disease. Proc Natl Acad Sci U S A. 2005;102:18129-18134.
94. Voss E, Wehkamp J, Wehkamp K, et al. NOD2/CARD15 mediates induction of the antimicrobial peptide human beta-defensin-2. J Biol Chem. 2006;281:2005-2011.
95. Ogushi K, Wada A, Niidome T, et al. Salmonella enteritidis FliC (flagella filament protein) induces human beta-defensin-2 mRNA production by Caco-2 cells. J Biol Chem. 2001;276:30521-30526.
96. Vora P, Youdim A, Thomas LS, et al. Beta-defensin-2 expression is regulated by TLR signaling in intestinal epithelial cells. J Immunol. 2004;173:5398-5405.
97. Wilson CL, Ouellette AJ, Satchell DP, et al. Regulation of intestinal alpha-defensin activation by the metalloproteinase matrilysin in innate host defense. Science. 1999;286:113-117.
98. Wilson IA. Perspectives: protein structure. Class-conscious TCR? Science. 1999;286:1867-1868.
99. Salzman NH, Ghosh D, Huttner KM, et al. Protection against enteric salmonellosis in transgenic mice expressing a human intestinal defensin. Nature. 2003;422:522-526.
100. Fukata M, Michelsen KS, Eri R, et al. 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. 2005;288:G1055-G1065.
101. Rachmilewitz D, Karmeli F, Takabayashi K, et al. Immunostimulatory DNA ameliorates experimental and spontaneous murine colitis. Gastroenterology. 2002;122:1428-1441.
102. Elson CO, Cong Y, McCracken VJ, et al. Experimental models of inflammatory bowel disease reveal innate, adaptive, and regulatory mechanisms of host dialogue with the microbiota. Immunol Rev. 2005;206:260-276.
103. Sansonetti PJ. War and peace at mucosal surfaces. Nat Rev Immunol. 2004;4:953-964.
104. Smith PD, Smythies LE, Mosteller-Barnum M, et al. Intestinal macrophages lack CD14 and CD89 and consequently are down-regulated for LPS- and IgA-mediated activities. J Immunol. 2001;167:2651-2656.
105. Abreu MT, Vora P, Faure E, et al. 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. 2001;167:1609-1616.
106. Naik S, Kelly EJ, Meijer L, et al. Absence of Toll-like receptor 4 explains endotoxin hyporesponsiveness in human intestinal epithelium. J Pediatr Gastroenterol Nutr. 2001;32:449-453.
107. Hornef MW, Frisan T, Vandewalle A, et al. Toll-like receptor 4 resides in the Golgi apparatus and colocalizes with internalized lipopolysaccharide in intestinal epithelial cells. J Exp Med. 2002;195:559-570.
108. Gewirtz AT, Navas TA, Lyons S, et al. Cutting edge: bacterial flagellin activates basolaterally expressed TLR5 to induce epithelial proinflammatory gene expression. J Immunol. 2001;167:1882-1885.
109. Gewirtz AT, Simon PO Jr, Schmitt CK, et al. Salmonella typhimurium translocates flagellin across intestinal epithelia, inducing a proinflammatory response. J Clin Invest. 2001;107:99-109.
110. Otte JM, Cario E, Podolsky DK. Mechanisms of cross hyporesponsiveness to Toll-like receptor bacterial ligands in intestinal epithelial cells. Gastroenterology. 2004;126:1054-1070.
111. Burns K, Clatworthy J, Martin L, et al. Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor. Nat Cell Biol. 2000;2:346-351.
112. Wald D, Qin J, Zhao Z, et al. SIGIRR, a negative regulator of Toll-like receptor-interleukin 1 receptor signaling. Nat Immunol. 2003;4:920-927.
113. Abreu MT, Arnold ET, Thomas LS, et al. TLR4 and MD-2 expression is regulated by immune-mediated signals in human intestinal epithelial cells. J Biol Chem. 2002;277:20431-20437.
114. Garlanda C, Riva F, Polentarutti N, et al. Intestinal inflammation in mice deficient in Tir8, an inhibitory member of the IL-1 receptor family. Proc Natl Acad Sci U S A. 2004;101:3522-3526.