Toll-like receptors (TLRs) and Nod-like receptors (NLRs) in inflammatory disorders

Seminars in Immunology - Tập 21 Số 4 - Trang 242-253 - 2009
Masayuki Fukata1, Arunan S. Vamadevan1, María T. Abreu1
1Division of Gastroenterology, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL 33136, United States

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Tài liệu tham khảo

Kawai, 2006, Innate immune recognition of viral infection, Nat Immunol, 7, 131, 10.1038/ni1303

Inohara, 2005, NOD–LRR proteins: role in host–microbial interactions and inflammatory disease, Annu Rev Biochem, 74, 355, 10.1146/annurev.biochem.74.082803.133347

Matzinger, 2002, The danger model: a renewed sense of self, Science, 296, 301, 10.1126/science.1071059

Shi, 2003, Molecular identification of a danger signal that alerts the immune system to dying cells, Nature, 425, 516, 10.1038/nature01991

Kanneganti, 2007, Pannexin-1-mediated recognition of bacterial molecules activates the cryopyrin inflammasome independent of Toll-like receptor signaling, Immunity, 26, 433, 10.1016/j.immuni.2007.03.008

Kawai, 2006, TLR signaling, Cell Death Differ, 13, 816, 10.1038/sj.cdd.4401850

O’Neill, 2006, How Toll-like receptors signal: what we know and what we don’t know, Curr Opin Immunol, 18, 3, 10.1016/j.coi.2005.11.012

Bowie, 2000, The interleukin-1 receptor/Toll-like receptor superfamily: signal generators for pro-inflammatory interleukins and microbial products, J Leukoc Biol, 67, 508, 10.1002/jlb.67.4.508

Creagh, 2006, TLRs, NLRs and RLRs: a trinity of pathogen sensors that co-operate in innate immunity, Trends Immunol, 27, 352, 10.1016/j.it.2006.06.003

Ting, 2006, CATERPILLERs, pyrin and hereditary immunological disorders, Nat Rev Immunol, 6, 183, 10.1038/nri1788

Harton, 2002, Cutting edge: CATERPILLER: a large family of mammalian genes containing CARD, pyrin, nucleotide-binding, and leucine-rich repeat domains, J Immunol, 169, 4088, 10.4049/jimmunol.169.8.4088

Inohara, 2003, Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease, J Biol Chem, 278, 5509, 10.1074/jbc.C200673200

Martinon, 2007, Inflammatory caspases and inflammasomes: master switches of inflammation, Cell Death Differ, 14, 10, 10.1038/sj.cdd.4402038

Chamaillard, 2003, Gene-environment interaction modulated by allelic heterogeneity in inflammatory diseases, Proc Natl Acad Sci USA, 100, 3455, 10.1073/pnas.0530276100

Ogura, 2003, Genetic variation and activity of mouse Nod2, a susceptibility gene for Crohn's disease small star, filled, Genomics, 81, 369, 10.1016/S0888-7543(03)00027-2

Windheim, 2007, Molecular mechanisms involved in the regulation of cytokine production by muramyl dipeptide, Biochem J, 404, 179, 10.1042/BJ20061704

Park, 2007, RICK/RIP2 mediates innate immune responses induced through Nod1 and Nod2 but not TLRs, J Immunol, 178, 2380, 10.4049/jimmunol.178.4.2380

Martinon, 2004, Inflammatory caspases: linking an intracellular innate immune system to autoinflammatory diseases, Cell, 117, 561, 10.1016/j.cell.2004.05.004

Agostini, 2004, NALP3 forms an IL-l beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder, Immunity, 20, 319, 10.1016/S1074-7613(04)00046-9

Sidiropoulos, 2008, Inflammasomes and rheumatic diseases: evolving concepts, Ann Rheum Dis, 67, 1382, 10.1136/ard.2007.078014

Steimle, 1993, Complementation cloning of an MHC class II transactivator mutated in hereditary MHC class II deficiency (or bare lymphocyte syndrome), Cell, 75, 135, 10.1016/S0092-8674(05)80090-X

Reith, 2001, The bare lymphocyte syndrome and the regulation of MHC expression, Annu Rev Immunol, 19, 331, 10.1146/annurev.immunol.19.1.331

Linhoff, 2001, Two distinct domains within CIITA mediate self-association: involvement of the GTP-binding and leucine-rich repeat domains, Mol Cell Biol, 21, 3001, 10.1128/MCB.21.9.3001-3011.2001

Nickerson, 2001, Dendritic cell-specific MHC class II transactivator contains a caspase recruitment domain that confers potent transactivation activity, J Biol Chem, 276, 19089, 10.1074/jbc.M101295200

Rao, 2007, IL-1 alpha and IL-1 ss are endogenous mediators linking cell injury to the adaptive alloimmune response, J Immunol, 179, 6536, 10.4049/jimmunol.179.10.6536

Acosta-Rodriguez, 2007, Interleukins 1 beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells, Nat Immunol, 8, 942, 10.1038/ni1496

Eisenbarth, 2008, Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants, Nature, 453, 10.1038/nature06939

Li, 2008, Cutting edge: inflammasome activation by alum and alum's adjuvant effect are mediated by NLRP3, J Immunol, 181, 17, 10.4049/jimmunol.181.1.17

Kool, 2008, Alum adjuvant boosts adaptive immunity by inducing uric acid and activating inflammatory dendritic cells, J Exp Med, 205, 869, 10.1084/jem.20071087

Schmitz, 2005, IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines, Immunity, 23, 479, 10.1016/j.immuni.2005.09.015

Mach, 1996, Regulation of MHC class II genes: lessons from a disease, Annu Rev Immunol, 14, 301, 10.1146/annurev.immunol.14.1.301

Fukata, 2008, The myeloid differentiation factor 88 (MyD88) is required for CD4(+) T cell effector function in a murine model of inflammatory bowel disease, J Immunol, 180, 1886, 10.4049/jimmunol.180.3.1886

Caron, 2005, Direct stimulation of human T cells via TLR5 and TLR7/8: flagellin and R-848 up-regulate proliferation and IFN-gamma production by memory CD4(+) T cells, J Immunol, 175, 1551, 10.4049/jimmunol.175.3.1551

Caramalho, 2003, Regulatory T cells selectively express toll-like receptors and are activated by lipopolysaccharide, J Exp Med, 197, 403, 10.1084/jem.20021633

Zarember, 2002, 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, J Immunol, 168, 554, 10.4049/jimmunol.168.2.554

Hugot, 2001, Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease, Nature, 411, 599, 10.1038/35079107

Ogura, 2001, A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease, Nature, 411, 603, 10.1038/35079114

McGovern, 2005, Association between a complex insertion/deletion polymorphism in NOD1 (CARD4) and susceptibility to inflammatory bowel disease, Hum Mol Genet, 14, 1245, 10.1093/hmg/ddi135

Elmaagacli, 2006, Mutations in innate immune system NOD2/CARD 15 and TLR-4 (Thr399Ile) genes influence the risk for severe acute graft-versus-host disease in patients who underwent an allogeneic transplantation, Transplantation, 81, 247, 10.1097/01.tp.0000188671.94646.16

Granell, 2006, Effect of NOD2/CARD15 variants in T-cell depleted allogeneic stem cell transplantation, Haematol-Hematol J, 91, 1372

Palmer, 2003, The role of innate immunity in acute allograft rejection after lung transplantation, Am J Respir Crit Care Med, 168, 628, 10.1164/rccm.200303-447OC

Miceli-Richard, 2001, CARD15 mutations in Blau syndrome, Nat Genet, 29, 19, 10.1038/ng720

Kanazawa, 2005, Early-onset sarcoidosis and CARD15 mutations with constitutive nuclear factor-kappa B activation: common genetic etiology with Blau syndrome, Blood, 105, 1195, 10.1182/blood-2004-07-2972

Rosenstiel, 2007, NOD-like receptors and human diseases, Microbes Infect, 9, 648, 10.1016/j.micinf.2007.01.015

Church, 2006, Hereditary auto-inflammatory disorders and biologics, Springer Semin Immunopathol, 27, 494, 10.1007/s00281-006-0015-6

Masters, 2006, Recent advances in the molecular pathogenesis of hereditary recurrent fevers, Curr Opin Allergy Clin Immunol, 6, 428, 10.1097/ACI.0b013e3280109b57

Dowds, 2004, Cryopyrin-induced interleukin 1 beta secretion in monocytic cells—enhanced activity of disease-associated mutants and requirement for ASC, J Biol Chem, 279, 21924, 10.1074/jbc.M401178200

Goldbach-Mansky, 2006, Neonatal-onset multisystem inflammatory disease responsive to interleukin-1 beta inhibition, N Engl J Med, 355, 581, 10.1056/NEJMoa055137

Hoffman, 2004, Prevention of cold-associated acute inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist, Lancet, 364, 1779, 10.1016/S0140-6736(04)17401-1

Jin, 2007, NALP1 in vitiligo-associated multiple autoimmune disease, N Engl J Med, 356, 1216, 10.1056/NEJMoa061592

Holt, 2002, Interactions between respiratory tract infections and atopy in the aetiology of asthma, Eur Respir J, 19, 538, 10.1183/09031936.02.00229302

Hysi, 2005, NOD1 variation, immunoglobulin E and asthma, Hum Mol Genet, 14, 935, 10.1093/hmg/ddi087

Eder, 2006, Association between exposure to farming, allergies and genetic variation in CARD4/NOD1, Allergy, 61, 1117, 10.1111/j.1398-9995.2006.01128.x

Girardin, 2005, Identification of the critical residues involved in peptidoglycan detection by Nod1, J Biol Chem, 280, 38648, 10.1074/jbc.M509537200

Weidinger, 2005, Association of CARD15 polymorphisms with atopy-related traits in a population-based cohort of Caucasian adults, Clin Exp Allergy, 35, 866, 10.1111/j.1365-2222.2005.02269.x

Woo, 2003, The-159C→T polymorphism of CD14 is associated with nonatopic asthma and food allergy, J Allergy Clin Immunol, 112, 438, 10.1067/mai.2003.1634

Leung T-f, 2005, CD14 and toll-like receptors: potential contribution of genetic factors and mechanisms to inflammation and allergy, Curr Drug Targets-Inflamm Allergy, 4, 169, 10.2174/1568010053586336

Woodcock, 2003, Control of exposure to mite allergen and allergen-impermeable bed covers for adults with asthma, N Engl J Med, 349, 225, 10.1056/NEJMoa023175

Eder, 2004, Toll-like receptor 2 as a major gene for asthma in children of European farmers, J Allergy Clin Immunol, 113, 482, 10.1016/j.jaci.2003.12.374

Lazarus, 2004, TOLL-like receptor 10 genetic variation is associated with asthma in two independent samples, Am J Respir Crit Care Med, 170, 594, 10.1164/rccm.200404-491OC

Hur, 2005, Association study of Toll-like receptor 9 gene polymorphism in Korean patients with systemic lupus erythematosus, Tissue Antigens, 65, 266, 10.1111/j.1399-0039.2005.00374.x

Sanchez, 2004, Polymorphisms of toll-like receptor 2 and 4 genes in rheumatoid arthritis and systemic lupus erythematosus, Tissue Antigens, 63, 54, 10.1111/j.1399-0039.2004.00162.x

Sheedy, 2008, The Mal/TIRAP S180L and TLR4 G299D polymorphisms are not associated with susceptibility to, or severity of, rheumatoid arthritis, Ann Rheum Dis, 67, 1328, 10.1136/ard.2007.083337

Steer, 2003, Development of rheumatoid arthritis is not associated with two polymorphisms in the Crohn's disease gene CARD15, Rheumatology (Oxford), 42, 304, 10.1093/rheumatology/keg091

Berdeli, 2005, TLR-2 gene Arg753Gln polymorphism is strongly associated with acute rheumatic fever in children, Journal of Molecular Medicine-JMM, 83, 535, 10.1007/s00109-005-0677-x

Kang, 2001, Detection of Toll-like receptor 2 (TLR2) mutation in the lepromatous leprosy patients, FEMS Immunol Med Microbiol, 31, 53, 10.1111/j.1574-695X.2001.tb01586.x

Franchimont, 2004, Deficient host–bacteria interactions in inflammatory bowel disease? The toll-like receptor (TLR)-4 Asp299Gly polymorphism is associated with Crohn's disease and ulcerative colitis, Gut, 53, 987, 10.1136/gut.2003.030205

Hausmann, 2002, Toll-like receptors 2 and 4 are up-regulated during intestinal inflammation, Gastroenterology, 122, 1987, 10.1053/gast.2002.33662

Kirino, 2008, Association of reduced heme oxygenase-1 with excessive Toll-like receptor 4 expression in peripheral blood mononuclear cells in Behcet's disease, Arthritis Res Ther, 10, 10.1186/ar2367

Do, 2008, Effects of vitamin D on expression of Toll-like receptors of monocytes from patients with Behcet's disease, Rheumatology (Oxford), 47, 840, 10.1093/rheumatology/ken109

Migita, 2007, Toll-like receptor expression in lupus peripheral blood mononuclear cells, J Rheumatol, 34, 493

Brentano, 2005, RNA released from necrotic synovial fluid cells activates rheumatoid arthritis synovial fibroblasts via Toll-like receptor 3, Arthritis Rheum, 52, 2656, 10.1002/art.21273

Kim, 2007, Human rheumatoid synovial fibroblasts promote osteoclastogenic activity by activating RANKL via TLR-2 and TLR-4 activation, Immunol Lett, 110, 54, 10.1016/j.imlet.2007.03.004

Marta, 2008, Unexpected regulatory roles of TLR4 and TLR9 in experimental autoimmune encephalomyelitis, Eur J Immunol, 38, 565, 10.1002/eji.200737187

Lampropoulou, 2008, TLR-activated B cells suppress T cell-mediated autoimmunity, J Immunol, 180, 4763, 10.4049/jimmunol.180.7.4763

Fitzgerald, 2007, Suppressive effect of IL-27 on encephalitogenic Th17 cells and the effector phase of experimental autoimmune encephalomyelitis, J Immunol, 179, 3268, 10.4049/jimmunol.179.5.3268

Nielsen, 2003, Upregulation of interleukin-12 and -17 in active inflammatory bowel disease, Scand J Gastroenterol, 38, 180, 10.1080/00365520310000672

Fujino, 2003, Increased expression of interleukin 17 in inflammatory bowel disease, Gut, 52, 65, 10.1136/gut.52.1.65

Tzartos, 2008, Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis, Am J Pathol, 172, 146, 10.2353/ajpath.2008.070690

Cho, 2004, Effector function of type II collagen-stimulated T cells from rheumatoid arthritis patients—cross-talk between T cells and synovial fibroblasts, Arthritis Rheum, 50, 776, 10.1002/art.20106

Ziolkowska, 2000, High levels of IL-17 in rheumatoid arthritis patients: IL-15 triggers in vitro IL-17 production via cyclosporin A-sensitive mechanism, J Immunol, 164, 2832, 10.4049/jimmunol.164.5.2832

Nakae, 2003, Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice, J Immunol, 171, 6173, 10.4049/jimmunol.171.11.6173

Lubberts, 2004, Treatment with a neutralizing anti-murine interleukin-17 antibody after the onset of collagen-induced arthritis reduces joint inflammation, cartilage destruction, and bone erosion, Arthritis Rheum, 50, 650, 10.1002/art.20001

Niebuhr, 2008, Impaired TLR-2 expression and TLR-2 mediated cytokine secretion in macrophages from patients with atopic dermatitis, Allergy, 63, 45

Eisenbarth, 2002, Lipopolysaccharide-enhanced, toll-like receptor 4-dependent T helper cell type 2 responses to inhaled antigen, J Exp Med, 196, 1645, 10.1084/jem.20021340

Dabbagh, 2002, Toll-like receptor 4 is required for optimal development of Th2 immune responses: role of dendritic cells, J Immunol, 168, 4524, 10.4049/jimmunol.168.9.4524

Piggott, 2005, MyD88-dependent induction of allergic Th2 responses to intranasal antigen, J Clin Invest, 115, 459, 10.1172/JCI200522462

Redecke, 2004, Cutting edge: activation of toll-like receptor 2 induces a Th2 immune response and promotes experimental asthma, J Immunol, 172, 2739, 10.4049/jimmunol.172.5.2739

Banerjee, 2004, Modulation of airway inflammation by immunostimulatory CpG oligodeoxynucleotides in a murine model of allergic aspergillosis, Infect Immun, 72, 6087, 10.1128/IAI.72.10.6087-6094.2004

Yamamoto, 2006, Modification of allergic inflammation in murine model of rhinitis by different bacterial ligands: involvement of mast cells and dendritic cells, Clin Exp Allergy, 36, 760, 10.1111/j.1365-2222.2006.02488.x

Dong, 2009, Different doses of lipopolysaccharides regulate the lung inflammation of asthmatic mice via TLR4 pathway in alveolar macrophages, J Asthma, 46, 229, 10.1080/02770900802610050

Lun, 2009, Expression and functional analysis of Toll-like receptors of peripheral blood cells in asthmatic patients: implication for immunopathological mechanism in asthma, J Clin Immunol, 29, 330, 10.1007/s10875-008-9269-1

Droemann, 2005, Toll-like receptor 2 expression is decreased on alveolar macrophages in cigarette smokers and COPD patients, Respir Res, 6

Pons, 2006, Expression of Toll-like receptor 2 is up-regulated in monocytes from patients with chronic obstructive pulmonary disease, Respir Res, 7

Sarir, 2008, Cells, mediators and Toll-like receptors in COPD, Eur J Pharmacol, 585, 346, 10.1016/j.ejphar.2008.03.009

Platz, 2004, Microbial DNA induces a host defense reaction of human respiratory epithelial cells, J Immunol, 173, 1219, 10.4049/jimmunol.173.2.1219

Sha, 2004, Activation of airway epithelial cells by toll-like receptor agonists, Am J Respir Cell Mol Biol, 31, 358, 10.1165/rcmb.2003-0388OC

Armstrong, 2004, Expression of functional toll-like receptor-2 and -4 on alveolar epithelial cells, Am J Respir Cell Mol Biol, 31, 241, 10.1165/rcmb.2004-0078OC

Guillot, 2005, Involvement of toll-like receptor 3 in the immune response of lung epithelial cells to double-stranded RNA and influenza A virus, J Biol Chem, 280, 5571, 10.1074/jbc.M410592200

Soong, 2004, TLR2 is mobilized into an apical lipid raft receptor complex to signal infection in airway epithelial cells, J Clin Invest, 113, 1482, 10.1172/JCI200420773

Fernandez, 2004, Inhibition of IL-10 receptor function in alveolar macrophages by toll-like receptor agonists, J Immunol, 172, 2613, 10.4049/jimmunol.172.4.2613

Haeberle, 2002, Respiratory syncytial virus-induced activation of nuclear factor-kappa B in the lung involves alveolar macrophages and toll-like receptor 4-dependent pathways, J Infect Dis, 186, 1199, 10.1086/344644

Doz, 2008, Cigarette smoke-induced pulmonary inflammation is TLR4/MyD88 and IL-1R1/MyD88 signaling dependent, J Immunol, 180, 1169, 10.4049/jimmunol.180.2.1169

Dostert, 2008, Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica, Science, 320, 674, 10.1126/science.1156995

Cassel, 2008, The Nalp3 inflammasome is essential for the development of silicosis, Proc Natl Acad Sci USA, 105, 9035, 10.1073/pnas.0803933105

Hornung, 2008, Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization, Nat Immunol, 9, 847, 10.1038/ni.1631

Wagner, 1997, Asbestosis and silicosis, Lancet, 349, 1311, 10.1016/S0140-6736(96)07336-9

Martinon, 2006, Gout-associated uric acid crystals activate the NALP3 inflammasome, Nature, 440, 237, 10.1038/nature04516

Kutzing, 2008, Altered uric acid levels and disease states, J Pharmacol Exp Ther, 324, 1, 10.1124/jpet.107.129031

McGonagle, 2008, Successful treatment of resistant pseudogout with anakinra, Arthritis Rheum, 58, 631, 10.1002/art.23119

McGonagle, 2007, Management of treatment resistant inflammation of acute on chronic tophaceous gout with anakinra, Ann Rheum Dis, 66, 1683, 10.1136/ard.2007.073759

Patole, 2007, Coactivation of Toll-like receptor-3 and -7 in immune complex glomerulonephritis, J Autoimmun, 29, 52, 10.1016/j.jaut.2007.04.004

Pawar, 2006, Microbial nucleic acids pay a Toll in kidney disease, Am J Physiol-Renal Physiol, 291, F509, 10.1152/ajprenal.00453.2005

Ehlers, 2007, Opposing effects of Toll-like receptor stimulation induce autoimmunity or tolerance, Trends Immunol, 28, 74, 10.1016/j.it.2006.12.006

Melmed, 2003, Human intestinal epithelial cells are broadly unresponsive to toll-like receptor 2-dependent bacterial ligands: implications for host–microbial interactions in the gut, J Immunol, 170, 1406, 10.4049/jimmunol.170.3.1406

Otte, 2004, Mechanisms of cross hyporesponsiveness to Toll-like receptor bacterial ligands in intestinal epithelial cells, Gastroenterology, 126, 1054, 10.1053/j.gastro.2004.01.007

Rock, 1998, A family of human receptors structurally related to Drosophila Toll, Proc Natl Acad Sci USA, 95, 588, 10.1073/pnas.95.2.588

Cario, 2000, Differential alteration in intestinal epithelial cell expression of toll-like receptor 3 (TLR3) and TLR4 in inflammatory bowel disease, Infect Immun, 68, 7010, 10.1128/IAI.68.12.7010-7017.2000

Abreu, 2002, TLR4 and MD-2 expression is regulated by immune-mediated signals in human intestinal epithelial cells, J Biol Chem, 277, 20431, 10.1074/jbc.M110333200

Suzuki, 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, 10.1128/IAI.71.6.3503-3511.2003

Browning, 2007, Has toll-like receptor 4 been prematurely dismissed as an inflammatory bowel disease gene? Association study combined with meta-analysis shows strong evidence for association, Am J Gastroenterol, 102, 2504, 10.1111/j.1572-0241.2007.01463.x

Brand, 2005, The role of Toll-like receptor 4 Asp299Gly and Thr399Ile polymorphisms and CARD15/NOD2 mutations in the susceptibility and phenotype of Crohn's disease, Inflamm Bowel Dis, 11, 645, 10.1097/01.MIB.0000168372.94907.d2

De Jager, 2007, The role of the Toll receptor pathway in susceptibility to inflammatory bowel diseases, Genes Immun, 8, 387, 10.1038/sj.gene.6364398

Ouburg, 2005, The toll-like receptor 4 (TLR4) Asp299Gly polymorphism is associated with colonic localisation of Crohn's disease without a major role for the Saccharomyces cerevisiae mannan-LBP-CD14-TLR4 pathway, Gut, 54, 439

Hume, 2008, Novel NOD2 haplotype strengthens the association between TLR4 Asp299Gly and Crohn's disease in an Australian population, Inflamm Bowel Dis, 14, 585, 10.1002/ibd.20362

Hong, 2007, TLR2,TLR4 and TLR9 polymorphisms and Crohn's disease in a New Zealand Caucasian cohort, J Gastroenterol Hepatol, 22, 1760, 10.1111/j.1440-1746.2006.04727.x

Török, 2009, Epistasis between Toll-like receptor-9 polymorphisms and variants in NOD2 and IL23R modulates susceptibility to Crohn's disease, Am J Gastroenterol, 10.1038/ajg.2009.184

Pierik, 2006, Toll-like receptor-1, -2, and -6 polymorphisms influence disease extension in inflammatory bowel diseases, Inflamm Bowel Dis, 12, 1, 10.1097/01.MIB.0000195389.11645.ab

Podolsky, 2009, Colitis-associated variant of TLR2 Causes impaired mucosal repair because of TFF3 Deficiency, Gastroenterology, 10.1053/j.gastro.2009.03.007

Hugot, 2001, Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease, Nature, 411, 599, 10.1038/35079107

Girardin, 2003, Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection, J Biol Chem, 278, 8869, 10.1074/jbc.C200651200

Netea, 2005, The frameshift mutation in Nod2 results in unresponsiveness not only to Nod2-but also Nod1-activating peptidoglycan agonists, J Biol Chem, 280, 35859, 10.1074/jbc.M504924200

Li, 2004, Regulation of IL-8 and IL-1beta expression in Crohn's disease associated NOD2/CARD15 mutations, Hum Mol Genet, 13, 1715, 10.1093/hmg/ddh182

Maeda, 2005, Nod2 mutation in Crohn's disease potentiates NF-kappaB activity and IL-1beta processing, Science, 307, 734, 10.1126/science.1103685

Kramer, 2006, Impaired dendritic cell function in Crohn's disease patients with NOD2 3020insC mutation, J Leukoc Biol, 79, 860, 10.1189/jlb.0805484

Lala, 2003, Crohn's disease and the NOD2 gene: a role for paneth cells, Gastroenterology, 125, 47, 10.1016/S0016-5085(03)00661-9

Seiderer, 2006, Homozygosity for the CARD15 frameshift mutation 1007fs is predictive of early onset of Crohn's disease with ileal stenosis, entero-enteral fistulas, and frequent need for surgical intervention with high risk of re-stenosis, Scand J Gastroenterol, 41, 1421, 10.1080/00365520600703900

Voss, 2006, NOD2/CARD15 mediates induction of the antimicrobial peptide human beta-defensin-2, J Biol Chem, 281, 2005, 10.1074/jbc.M511044200

Wehkamp, 2004, NOD2 (CARD15) mutations in Crohn's disease are associated with diminished mucosal alpha-defensin expression, Gut, 53, 1658, 10.1136/gut.2003.032805

Hisamatsu, 2003, CARD15/NOD2 functions as an antibacterial factor in human intestinal epithelial cells, Gastroenterology, 124, 993, 10.1053/gast.2003.50153

Devlin, 2007, NOD2 variants and antibody response to microbial antigens in Crohn's disease patients and their unaffected relatives, Gastroenterology, 132, 576, 10.1053/j.gastro.2006.11.013

Henckaerts, 2007, Mutations in pattern recognition receptor genes modulate seroreactivity to microbial antigens in patients with inflammatory bowel disease, Gut, 56, 1536, 10.1136/gut.2007.125468

Fukata, 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, 10.1152/ajpgi.00328.2004

Rakoff-Nahoum, 2004, Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis, Cell, 118, 229, 10.1016/j.cell.2004.07.002

Villani, 2009, Common variants in the NLRP3 region contribute to Crohn's disease susceptibility, Nat Genet, 41, 71, 10.1038/ng.285

Romagne, 2007, Current and future drugs targeting one class of innate immunity receptors: the Toll-like receptors, Drug Discov Today, 12, 80, 10.1016/j.drudis.2006.11.007

Picard, 2003, Pyogenic bacterial infections in humans with IRAK-4 deficiency, Science, 299, 2076, 10.1126/science.1081902

Ungaro, 2009, A novel Toll-like receptor 4 antagonist antibody ameliorates inflammation but impairs mucosal healing in murine colitis, Am J Physiol Gastrointest Liver Physiol, 296, G1167, 10.1152/ajpgi.90496.2008

Pawar, 2006, Ligands to nucleic acid-specific toll-like receptors and the onset of lupus nephritis, J Am Soc Nephrol, 17, 3365, 10.1681/ASN.2006030263

Tulic, 2004, Amb a 1-immunostimulatory oligodeoxynucleotide conjugate immunotherapy decreases the nasal inflammatory response, J Allergy Clin Immunol, 113, 235, 10.1016/j.jaci.2003.11.001

Creticos, 2006, Immunotherapy with a ragweed-toll-like receptor 9 agonist vaccine for allergic rhinitis, N Engl J Med, 355, 1445, 10.1056/NEJMoa052916

Gauvreau, 2006, Immunostimulatory sequences regulate interferon-inducible genes but not allergic airway responses, Am J Respir Crit Care Med, 174, 15, 10.1164/rccm.200601-057OC

Brugnolo, 2003, The novel synthetic immune response modifier R-848 (Resiquimod) shifts human allergen-specific CD4+ TH2 lymphocytes into IFN-gamma-producing cells, J Allergy Clin Immunol, 111, 380, 10.1067/mai.2003.102

Moisan, 2006, TLR7 ligand prevents allergen-induced airway hyperresponsiveness and eosinophilia in allergic asthma by a MYD88-dependent and MK2-independent pathway, Am J Physiol-Lung Cell Mol Physiol, 290, L987, 10.1152/ajplung.00440.2005

Barrat, 2005, Nucleic acids of mammalian origin can act as endogenous ligands for toll-like receptors and may promote systemic lupus erythematosus, J Exp Med, 202, 1131, 10.1084/jem.20050914

Rossignol, 2004, Safety, pharmacokinetics, pharmacodynamics, and plasma lipoprotein distribution of eritoran (E5564) during continuous intravenous infusion into healthy volunteers, Antimicrob Agents Chemother, 48, 3233, 10.1128/AAC.48.9.3233-3240.2004

Schiff, 2000, Role of interleukin 1 and interleukin 1 receptor antagonist in the mediation of rheumatoid arthritis, Ann Rheum Dis, 59, i103, 10.1136/ard.59.suppl_1.i103

Naik, 2008, Biologic therapeutics in thyroid-associated ophthalmopathy: translating disease mechanism into therapy, Thyroid, 18, 967, 10.1089/thy.2007.0403

Glaser, 2008, The spectrum of monogenic autoinflammatory syndromes: understanding disease mechanisms and use of targeted therapies, Curr Allergy Asthma Rep, 8, 288, 10.1007/s11882-008-0047-1

Carroll, 2008, Signalling, inflammation and arthritis—crossed signals: the role of interleukin-15 and-18 in autoimmunity, Rheumatology (Oxford), 47, 1269, 10.1093/rheumatology/ken257

Boraschi, 2006, IL-18 in autoimmunity: review, Eur Cytokine Netw, 17, 224

Karanikolas, 2008, Adjunctive anakinra in patients with active rheumatoid arthritis despite methotrexate, or leflunomide, or cyclosporin-A monotherapy: a 48-week, comparative, prospective study, Rheumatology (Oxford), 47, 1384, 10.1093/rheumatology/ken223

Bresnihan, 1998, Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist, Arthritis Rheum, 41, 2196, 10.1002/1529-0131(199812)41:12<2196::AID-ART15>3.0.CO;2-2

Cohen, 2002, Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist, in combination with methotrexate—results of a twenty-four-week, multicenter, randomized, double-blind, placebo-controlled trial, Arthritis Rheum, 46, 614, 10.1002/art.10141

Fleischmann, 2004, Anakinra: an inhibitor of IL-1 for the treatment of rheumatoid arthritis, Exp Opin Biol Ther, 4, 1333, 10.1517/14712598.4.8.1333

Obermeier, 2003, Contrasting activity of cytosin-guanosin dinucleotide oligonucleotides in mice with experimental colitis, Clin Exp Immunol, 134, 217, 10.1046/j.1365-2249.2003.02288.x

Rachmilewitz, 2004, Toll-like receptor 9 signaling mediates the anti-inflammatory effects of probiotics in murine experimental colitis, Gastroenterology, 126, 520, 10.1053/j.gastro.2003.11.019

Vijay-Kumar, 2008, Flagellin treatment protects against chemicals, bacteria, viruses, and radiation, J Immunol, 180, 8280, 10.4049/jimmunol.180.12.8280

Vijay-Kumar, 2007, Activation of toll-like receptor 3 protects against DSS-induced acute colitis, Inflamm Bowel Dis, 13, 856, 10.1002/ibd.20142

Watanabe, 2008, Muramyl dipeptide activation of nucleotide-binding oligomerization domain 2 protects mice from experimental colitis, J Clin Invest, 118, 545

Alexopoulou, 2001, Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3, Nature, 413, 732, 10.1038/35099560

Asea, 2002, Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4, J Biol Chem, 277, 15028, 10.1074/jbc.M200497200

Campos, 2001, Activation of Toll-like receptor-2 by glycosylphosphatidylinositol anchors from a protozoan parasite, J Immunol, 167, 416, 10.4049/jimmunol.167.1.416

Gomi, 2002, Toll-like receptor 4-MD-2 complex mediates the signal transduction induced by flavolipin, an amino acid-containing lipid unique to Flavobacterium meningosepticum, J Immunol, 168, 2939, 10.4049/jimmunol.168.6.2939

Hajjar, 2001, Cutting edge: functional interactions between toll-like receptor (TLR) 2 and TLR1 or TLR6 in response to phenol-soluble modulin, J Immunol, 166, 15, 10.4049/jimmunol.166.1.15

Heil, 2004, Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8, Science, 303, 1526, 10.1126/science.1093620

Hemmi, 2000, A Toll-like receptor recognizes bacterial DNA, Nature, 408, 740, 10.1038/35047123

Johnson, 2002, Receptor-mediated monitoring of tissue well-being via detection of soluble heparan sulfate by Toll-like receptor 4, J Immunol, 168, 5233, 10.4049/jimmunol.168.10.5233

Kawasaki, 2000, Mouse toll-like receptor 4,MD-2 complex mediates lipopolysaccharide-mimetic signal transduction by Taxol, J Biol Chem, 275, 2251, 10.1074/jbc.275.4.2251

Kurt-Jones, 2000, Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus, Nat Immunol, 1, 398, 10.1038/80833

Massari, 2002, Cutting edge: immune stimulation by neisserial porins is toll-like receptor 2 and MyD88 dependent, J Immunol, 168, 1533, 10.4049/jimmunol.168.4.1533

Ohashi, 2000, Cutting edge: heat shock protein 60 is a putative endogenous ligand of the toll-like receptor-4 complex, J Immunol, 164, 558, 10.4049/jimmunol.164.2.558

Okamura, 2001, The extra domain A of fibronectin activates Toll-like receptor 4, J Biol Chem, 276, 10229, 10.1074/jbc.M100099200

Opitz, 2001, Toll-like receptor-2 mediates Treponema glycolipid and lipoteichoic acid-induced NF-kappaB translocation, J Biol Chem, 276, 22041, 10.1074/jbc.M010481200

Ozinsky, 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 USA, 97, 13766, 10.1073/pnas.250476497

Rassa, 2002, Murine retroviruses activate B cells via interaction with toll-like receptor 4, Proc Natl Acad Sci USA, 99, 2281, 10.1073/pnas.042355399

Scheibner, 2006, Hyaluronan fragments act as an endogenous danger signal by engaging TLR2, J Immunol, 177, 1272, 10.4049/jimmunol.177.2.1272

Schwandner, 1999, Peptidoglycan- and lipoteichoic acid-induced cell activation is mediated by toll-like receptor 2, J Biol Chem, 274, 17406, 10.1074/jbc.274.25.17406

Smiley, 2001, Fibrinogen stimulates macrophage chemokine secretion through toll-like receptor 4, J Immunol, 167, 2887, 10.4049/jimmunol.167.5.2887

Takeuchi, 1999, Differential roles of TLR2 and TLR4 in recognition of Gram-negative and Gram-positive bacterial cell wall components, Immunity, 11, 443, 10.1016/S1074-7613(00)80119-3

Takeuchi, 2001, Discrimination of bacterial lipoproteins by Toll-like receptor 6, Int Immunol, 13, 933, 10.1093/intimm/13.7.933

Takeuchi, 2002, Cutting edge: role of Toll-like receptor 1 in mediating immune response to microbial lipoproteins, J Immunol, 169, 10, 10.4049/jimmunol.169.1.10

Termeer, 2002, Oligosaccharides of Hyaluronan activate dendritic cells via toll-like receptor 4, J Exp Med, 195, 99, 10.1084/jem.20001858

Uematsu, 2008, Toll-like receptors (TLRs) and their ligands, Handb Exp Pharmacol, 1, 10.1007/978-3-540-72167-3_1

Underhill, 1999, The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens, Nature, 401, 811, 10.1038/44605

Wyllie, 2000, Evidence for an accessory protein function for Toll-like receptor 1 in anti-bacterial responses, J Immunol, 165, 7125, 10.4049/jimmunol.165.12.7125

Shaw, 2008, NOD-like receptors (NLRs): bona fide intracellular microbial sensors, Curr Opin Immunol, 20, 377, 10.1016/j.coi.2008.06.001

Akira, 2006, Pathogen recognition and innate immunity, Cell, 124, 783, 10.1016/j.cell.2006.02.015

Tanabe, 2004, Regulatory regions and critical residues of NOD2 involved in muramyl dipeptide recognition, Embo J, 23, 1587, 10.1038/sj.emboj.7600175

Inohara, 2003, NODs: intracellular proteins involved in inflammation and apoptosis, Nat Rev Immunol, 3, 371, 10.1038/nri1086

Ting, 2008, The NLR gene family: a standard nomenclature, Immunity, 28, 285, 10.1016/j.immuni.2008.02.005

Tattoli, 2008, NLRX1 is a mitochondrial NOD-like receptor that amplifies NF-kappa B and JNK pathways by inducing reactive oxygen species production, Embo Reports, 9, 293, 10.1038/sj.embor.7401161

Barnich, 2005, Membrane recruitment of NOD2 in intestinal epithelial cells is essential for nuclear factor-kappa B activation in muramyl dipeptide recognition, J Cell Biol, 170, 21, 10.1083/jcb.200502153

Uehara, 2005, Chemically synthesized pathogen-associated molecular patterns increase the expression of peptidoglycan recognition proteins via Toll-like receptors, NOD1 and NOD2 in human oral epithelial cells, Cell Microbiol, 7, 675, 10.1111/j.1462-5822.2004.00500.x

Hsu, 2008, A NOD2–NALP1 complex mediates caspase-1-dependent IL-1 beta secretion in response to Bacillus anthracis infection and muramyl dipeptide, Proc Natl Acad Sci USA, 105, 7803, 10.1073/pnas.0802726105

Girardin, 2003, Nod1 detects a unique muropeptide from gram-negative bacterial peptidoglycan, Science, 300, 1584, 10.1126/science.1084677

Windheim, 2007, Molecular mechanisms involved in the regulation of cytokine production by muramyl dipeptide, Biochem J, 404, 179, 10.1042/BJ20061704

Boyden, 2006, Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin, Nat Genet, 38, 240, 10.1038/ng1724

Chamaillard, 2003, An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid, Nat Immunol, 4, 702, 10.1038/ni945

Ferwerda, 2005, NOD2 and toll-like receptors are nonredundant recognition systems of Mycobacterium tuberculosis, Plos Pathogens, 1, 279, 10.1371/journal.ppat.0010034

Franchi, 2006, Nucleotide-binding oligomerization domain-like receptors: intracellular pattern recognition molecules for pathogen detection and host defense, J Immunol, 177, 3507, 10.4049/jimmunol.177.6.3507

Heinzelmann, 2000, Endotoxin and muramyl dipeptide modulate surface receptor expression on human mononuclear cells, Immunopharmacology, 48, 117, 10.1016/S0162-3109(00)00195-8

Viala, 2004, Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island, Nat Immunol, 5, 1166, 10.1038/ni1131

Becker, 2007, Inflammasomes in inflammatory disorders: the role of TLRs and their interactions with NLRs, Semin Immunopathol, 29, 239, 10.1007/s00281-007-0081-4

Fischer, 2008, Toll-like receptors in autoimmunity, Year Immunol, 1143, 21

Kanczkowski, 2008, Toll-like receptors in endocrine disease and diabetes, Neuroimmunomodulation, 15, 54, 10.1159/000135624

Raschi, 2008, Toll-like receptors: another player in the pathogenesis of the anti-phospholipid syndrome, Lupus, 17, 937, 10.1177/0961203308095140

Dowds, 2003, Regulation of cryopyrin/Pypaf1 signaling by pyrin, the familial Mediterranean fever gene product, Biochem Biophys Res Commun, 302, 575, 10.1016/S0006-291X(03)00221-3

Kanneganti, 2007, Intracellular NOD-like receptors in host defense and disease, Immunity, 27, 549, 10.1016/j.immuni.2007.10.002

Kullberg, 2008, Crohn's disease patients homozygous for the 3020insC NOD2 mutation have a defective NOD2/TLR4 cross-tolerance to intestinal stimuli, Immunology, 123, 600, 10.1111/j.1365-2567.2007.02735.x

Petrilli, 2007, The inflammasome: a danger sensing complex triggering innate immunity, Curr Opin Immunol, 19, 615, 10.1016/j.coi.2007.09.002

Rosenstiel, 2008, NOD-like receptors: ancient sentinels of the innate immune system, Cell Mol Life Sci, 65, 1361, 10.1007/s00018-008-7502-y

Weidinger, 2005, Association of NOD1 polymorphisms with atopic eczema and related phenotypes, J Allergy Clin Immunol, 116, 177, 10.1016/j.jaci.2005.02.034

Lahiri, 2008, Engagement of TLR signaling as adjuvant: towards smarter vaccine and beyond, Vaccine, 26, 6777, 10.1016/j.vaccine.2008.09.045

Barrat, 2008, Development of TLR inhibitors for the treatment of autoimmune diseases, Immunol Rev, 223, 271, 10.1111/j.1600-065X.2008.00630.x

Schmidt, 2006, Toll-like receptor therapies compete to reduce side effects, Nat Biotechnol, 24, 230, 10.1038/nbt0306-230

Jasani, 2009, Ampligen: a potential toll-like 3 receptor adjuvant for immunotherapy of cancer, Vaccine, 27, 3401, 10.1016/j.vaccine.2009.01.071