O'Neill, L. Targeting signal transduction as a strategy to treat inflammatory diseases. Nature Rev. Drug Discov.5, 549–563 (2006). CAS Google Scholar
Koropatnick, T. A. et al. Microbial factor-mediated development in a host–bacterial mutualism. Science306, 1186–1188 (2004). CASPubMed Google Scholar
Park, B. S. et al. The structural basis of lipopolysaccharide recognition by the TLR4–MD-2 complex. Nature458, 1191–1195 (2009). References 3, 6 and 7 are the first studies to illustrate the crystal structures for TLR4, TLR3 and the TLR1–TLR2 heterodimer with their specific ligands. CASPubMed Google Scholar
Dziarski, R. & Gupta, D. Role of MD-2 in TLR2- and TLR4-mediated recognition of Gram-negative and Gram-positive bacteria and activation of chemokine genes. J. Endotoxin Res.6, 401–405 (2000). CASPubMed Google Scholar
Carpenter, S. & O'Neill, L. A. Recent insights into the structure of Toll-like receptors and post-translational modifications of their associated signalling proteins. Biochem. J.422, 1–10 (2009). CASPubMed Google Scholar
Liu, L. et al. Structural basis of toll-like receptor 3 signaling with double-stranded RNA. Science320, 379–381 (2008). CASPubMedPubMed Central Google Scholar
Jin, M. S. et al. Crystal structure of the TLR1–TLR2 heterodimer induced by binding of a tri-acylated lipopeptide. Cell130, 1071–1082 (2007). CASPubMed Google Scholar
Kawai, T. & Akira, S. TLR signaling. Cell Death Differ.13, 816–825 (2006). CASPubMed Google Scholar
Somani, N. & Rivers, J. K. Imiquimod 5% cream for the treatment of actinic keratoses. Skin Therapy Lett.10, 1–6 (2005). CASPubMed Google Scholar
Stockfleth, E., Christophers, E., Benninghoff, B. & Sterry, W. Low incidence of new actinic keratoses after topical 5% imiquimod cream treatment: a long-term follow-up study. Arch. Dermatol.140, 1542 (2004). PubMed Google Scholar
Larange, A., Antonios, D., Pallardy, M. & Kerdine-Romer, S. TLR7 and TLR8 agonists trigger different signaling pathways for human dendritic cell maturation. J. Leukoc. Biol.85, 673–683 (2009). CASPubMed Google Scholar
Lysa, B. et al. Gene expression in actinic keratoses: pharmacological modulation by imiquimod. Br. J. Dermatol.151, 1150–1159 (2004). CASPubMed Google Scholar
Schwartz, D. & Cook, D. Polymorphisms of the Toll-like receptors and human disease. Clin. Infect. Dis.41 (Suppl. 7), 403–407 (2005). Google Scholar
Ishii, K. J. & Akira, S. Toll or toll-free adjuvant path toward the optimal vaccine development. J. Clin. Immunol.27, 363–371 (2007). CASPubMed Google Scholar
Ehlers, M. & Ravetch, J. V. Opposing effects of Toll-like receptor stimulation induce autoimmunity or tolerance. Trends Immunol.28, 74–79 (2007). CASPubMed Google Scholar
Meneghin, A. & Hogaboam, C. M. Infectious disease, the innate immune response, and fibrosis. J. Clin. Invest.117, 530–538 (2007). CASPubMedPubMed Central Google Scholar
Rakoff-Nahoum, S. & Medzhitov, R. Toll-like receptors and cancer. Nature Rev. Cancer9, 57–63 (2009). CAS Google Scholar
Cho, Y. J., Ahn, B. Y., Lee, N. G., Lee, D. H. & Kim, D. S. A combination of E. coli DNA fragments and modified lipopolysaccharides as a cancer immunotherapy. Vaccine24, 5862–5871 (2006). CASPubMed Google Scholar
Wei, M. Q., Mengesha, A., Good, D. & Anne, J. Bacterial targeted tumour therapy — dawn of a new era. Cancer Lett.259, 16–27 (2008). CASPubMed Google Scholar
Hemmi, H. et al. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nature Immunol.3, 196–200 (2002). CAS Google Scholar
O'Neill, L. A., Bryant, C. E. & Doyle, S. L. Therapeutic targeting of toll-like receptors for infectious and inflammatory diseases and cancer. Pharmacol. Rev.61, 177–197 (2009). CASPubMedPubMed Central Google Scholar
Lan, T. et al. Stabilized immune modulatory RNA compounds as agonists of Toll-like receptors 7 and 8. Proc. Natl Acad. Sci. USA104, 13750–13755 (2007). CASPubMedPubMed Central Google Scholar
Dudek, A. Z. et al. First in human phase I trial of 852A, a novel systemic toll-like receptor 7 agonist, to activate innate immune responses in patients with advanced cancer. Clin. Cancer Res.13, 7119–7125 (2007). CASPubMed Google Scholar
Dummer, R. et al. An exploratory study of systemic administration of the toll-like receptor-7 agonist 852A in patients with refractory metastatic melanoma. Clin. Cancer Res.14, 856–864 (2008). CASPubMed Google Scholar
Harrison, L. I., Astry, C., Kumar, S. & Yunis, C. Pharmacokinetics of 852A, an imidazoquinoline Toll-like receptor 7-specific agonist, following intravenous, subcutaneous, and oral administrations in humans. J. Clin. Pharmacol.47, 962–969 (2007). CASPubMed Google Scholar
Agrawal, S. & Kandimalla, E. R. Synthetic agonists of Toll-like receptors 7, 8 and 9. Biochem. Soc. Trans.35, 1461–1467 (2007). CASPubMed Google Scholar
Goodchild, A. et al. Primary leukocyte screens for innate immune agonists. J. Biomol. Screen14, 723–730 (2009). CASPubMed Google Scholar
Krieg, A. M. Toll-like receptor 9 (TLR9) agonists in the treatment of cancer. Oncogene27, 161–167 (2008). CASPubMed Google Scholar
Kochling, J. et al. Anti-tumor effect of DNA-based vaccination and dSLIM immunomodulatory molecules in mice with Ph+ acute lymphoblastic leukaemia. Vaccine26, 4669–4675 (2008). PubMed Google Scholar
Vollmer, J. et al. Characterization of three CpG oligodeoxynucleotide classes with distinct immunostimulatory activities. Eur. J. Immunol.34, 251–262 (2004). CASPubMed Google Scholar
Dorn, A. & Kippenberger, S. Clinical application of CpG-, non-CpG-, and antisense oligodeoxynucleotides as immunomodulators. Curr. Opin. Mol. Ther.10, 10–20 (2008). CASPubMed Google Scholar
Schmidt, C. Clinical setbacks for toll-like receptor 9 agonists in cancer. Nature Biotech.25, 825–826 (2007). CAS Google Scholar
Salaun, B., Coste, I., Rissoan, M. C., Lebecque, S. J. & Renno, T. TLR3 can directly trigger apoptosis in human cancer cells. J. Immunol.176, 4894–4901 (2006). CASPubMed Google Scholar
Panter G., K. A., Jerala R. Therapeutic applications of nucleic acids as ligands for Toll-like receptors. Curr. Opin. Mol. Ther.11, 133–145 (2009). CASPubMed Google Scholar
D'Agostini, C. et al. Antitumour effect of OM-174 and cyclophosphamide on murine B16 melanoma in different experimental conditions. Int. Immunopharmacol.5, 1205–1212 (2005). CASPubMed Google Scholar
Garay, R. P. et al. Cancer relapse under chemotherapy: why TLR2/4 receptor agonists can help. Eur. J. Pharmacol.563, 1–17 (2007). CASPubMed Google Scholar
De Ridder, M. et al. The radiosensitizing effect of immunoadjuvant OM-174 requires cooperation between immune and tumor cells through interferon-γ and inducible nitric oxide synthase. Int. J. Radiat. Oncol. Biol. Phys.66, 1473–1480 (2006). CASPubMed Google Scholar
Apetoh, L. et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nature Med.13, 1050–1059 (2007). CASPubMed Google Scholar
Simons, M. P., O'Donnell, M. A. & Griffith, T. S. Role of neutrophils in BCG immunotherapy for bladder cancer. Urol. Oncol.26, 341–345 (2008). CASPubMedPubMed Central Google Scholar
Murata, M. Activation of Toll-like receptor 2 by a novel preparation of cell wall skeleton from Mycobacterium bovis BCG Tokyo (SMP-105) sufficiently enhances immune responses against tumors. Cancer Sci.99, 1435–1440 (2008). CASPubMed Google Scholar
Burdelya, L. G. et al. An agonist of toll-like receptor 5 has radioprotective activity in mouse and primate models. Science320, 226–230 (2008). CASPubMedPubMed Central Google Scholar
Sfondrini, L. et al. Antitumor activity of the TLR-5 ligand flagellin in mouse models of cancer. J. Immunol.176, 6624–6630 (2006). CASPubMed Google Scholar
Parkinson, T. The future of toll-like receptor therapeutics. Curr. Opin. Mol. Ther.10, 21–31 (2008). CASPubMed Google Scholar
Schalm, S. W. et al. Ribavirin enhances the efficacy but not the adverse effects of interferon in chronic hepatitis C. Meta-analysis of individual patient data from European centers. J. Hepatol.26, 961–966 (1997). CASPubMed Google Scholar
Mark, K. E. et al. Topical resiquimod 0.01% gel decreases herpes simplex virus type 2 genital shedding: a randomized, controlled trial. J. Infect. Dis.195, 1324–1331 (2007). CASPubMed Google Scholar
Pockros, P. J. et al. Oral resiquimod in chronic HCV infection: safety and efficacy in 2 placebo-controlled, double-blind phase IIa studies. J. Hepatol.47, 174–182 (2007). CASPubMed Google Scholar
Caron, G. et al. Direct stimulation of human T cells via TLR5 and TLR7/8: flagellin and R-848 up-regulate proliferation and IFN-γ production by memory CD4+ T cells. J. Immunol.175, 1551–1557 (2005). CASPubMed Google Scholar
Kronenberger, B. & Zeuzem, S. Current and future treatment options for HCV. Ann. Hepatol.8, 103–112 (2009). PubMed Google Scholar
Barry, M. & Cooper, C. Review of hepatitis B surface antigen-1018 ISS adjuvant-containing vaccine safety and efficacy. Expert Opin. Biol. Ther.7, 1731–1737 (2007). CASPubMed Google Scholar
Harandi, A. M., Davies, G. & Olesen, O. F. Vaccine adjuvants: scientific challenges and strategic initiatives. Expert Rev. Vaccines8, 293–298 (2009). CASPubMed Google Scholar
Gu, M., Hine, P. M., James Jackson, W., Giri, L. & Nabors, G. S. Increased potency of BioThrax anthrax vaccine with the addition of the C-class CpG oligonucleotide adjuvant CPG 10109. Vaccine25, 526–534 (2007). CASPubMed Google Scholar
Krieg, A. M. Toll-free vaccines? Nature Biotech.25, 303–305 (2007). CAS Google Scholar
Mata-Haro, V. et al. The vaccine adjuvant monophosphoryl lipid A as a TRIF-biased agonist of TLR4. Science316, 1628–1632 (2007). This study showed that the vaccine adjuvant MPLA has a bias towards TRIF-dependent signalling, which has important implications for the development of future therapies. CASPubMed Google Scholar
Gavin, A. L. et al. Adjuvant-enhanced antibody responses in the absence of toll-like receptor signaling. Science314, 1936–1938 (2006). CASPubMedPubMed Central Google Scholar
van Duin, D., Medzhitov, R. & Shaw, A. C. Triggering TLR signaling in vaccination. Trends Immunol.27, 49–55 (2006). CASPubMed Google Scholar
Jasani, B., Navabi, H. & Adams, M. Ampligen: a potential toll-like 3 receptor adjuvant for immunotherapy of cancer. Vaccine27, 3401–3404 (2009). CASPubMed Google Scholar
Navabi, H. et al. A clinical grade poly I:C-analogue (Ampligen) promotes optimal DC maturation and Th1-type T cell responses of healthy donors and cancer patients in vitro. Vaccine27, 107–115 (2009). A poly I:C analogue which stimulates dendritic cell maturation and IL-12 and induces much lower levels of IL-10 compared with poly I:C, has shown great promise as an adjuvant for cancer therapies. CASPubMed Google Scholar
Huleatt, J. W. et al. Potent immunogenicity and efficacy of a universal influenza vaccine candidate comprising a recombinant fusion protein linking influenza M2e to the TLR5 ligand flagellin. Vaccine26, 201–214 (2008). This study showed that the use of a TLR-specific ligand coupled to an influenza protein can offer widespread protection against strains of influenza A. CASPubMed Google Scholar
Kanzler, H., Barrat, F. J., Hessel, E. M. & Coffman, R. L. Therapeutic targeting of innate immunity with Toll-like receptor agonists and antagonists. Nature Med.13, 552–559 (2007). CASPubMed Google Scholar
Gangloff, S. C. & Guenounou, M. Toll-like receptors and immune response in allergic disease. Clin. Rev. Allergy Immunol.26, 115–125 (2004). CASPubMed Google Scholar
Kline, J. N. & Krieg, A. M. Toll-like receptor 9 activation with CpG oligodeoxynucleotides for asthma therapy. Drug News Perspect.21, 434–439 (2008). CASPubMed Google Scholar
Heijink, I. H. & Van Oosterhout, A. J. Strategies for targeting T-cells in allergic diseases and asthma. Pharmacol. Ther.112, 489–500 (2006). CASPubMed Google Scholar
Pastorelli, L., Pizarro, T. T., Cominelli, F. & Vecchi, M. Emerging drugs for the treatment of ulcerative colitis. Expert Opin. Emerg. Drugs14, 505–521 (2009). CASPubMedPubMed Central Google Scholar
Baldrick, P., Richardson, D., Woroniecki, S. R. & Lees, B. Pollinex Quattro Ragweed: safety evaluation of a new allergy vaccine adjuvanted with monophosphoryl lipid A (MPL) for the treatment of ragweed pollen allergy. J. Appl. Toxicol.27, 399–409 (2007). CASPubMed Google Scholar
DuBuske L. M., C. M.a.H. T. Significant reduction in combined symptom and medication score compared with placebo following MPL-adjuvanted uSCIT in patients with seasonal grass pollen allergy. J. of Allergy Clin. Immunol.123, S216–S216 (2009). Google Scholar
Feldmann, M. Translating molecular insights in autoimmunity into effective therapy. Annu. Rev. Immunol.27, 1–27 (2009). CASPubMed Google Scholar
Klareskog, L. et al. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet363, 675–681 (2004). CASPubMed Google Scholar
van der Heijde, D. et al. Inhibition of radiographic progression with combination etanercept and methotrexate in patients with moderately active rheumatoid arthritis previously treated with monotherapy. Ann. Rheum. Dis.68, 1113–1118 (2009). This study demonstrates that the use of a combination therapy consisting of the antiTNF drug etanercept and methotrexate is much more efficacious in treating patients with moderate rheumatoid arthritis than either therapy alone. CASPubMed Google Scholar
Macfarlane, D. E. & Manzel, L. Antagonism of immunostimulatory CpG-oligodeoxynucleotides by quinacrine, chloroquine, and structurally related compounds. J. Immunol.160, 1122–1131 (1998). CASPubMed Google Scholar
Sun, S., Rao, N. L., Venable, J., Thurmond, R. & Karlsson, L. TLR7/9 antagonists as therapeutics for immune-mediated inflammatory disorders. Inflamm. Allergy Drug Targets6, 223–235 (2007). CASPubMed Google Scholar
Lipford G. et al. Selective Toll-like receptor 7/8/9 antagonists for the oral treatment of autoimmune diseases. American College of Rheumatology 2007 Annual Scientific Meeting (2007). ACR website [online], (2007). Google Scholar
Barrat, F. J., Meeker, T., Chan, J. H., Guiducci, C. & Coffman, R. L. Treatment of lupus-prone mice with a dual inhibitor of TLR7 and TLR9 leads to reduction of autoantibody production and amelioration of disease symptoms. Eur. J. Immunol.37, 3582–3586 (2007). This study showed that in plasmacytoid dendritic cells isolated from patients with SLE, the TLR7 and TLR9 inhibitor IRS954 inhibited the production of IFNα in response to DNA and RNA from viruses. The compound prevented disease progression in SLE-prone mice. CASPubMed Google Scholar
Pawar, R. D. et al. Inhibition of Toll-like receptor-7 (TLR-7) or TLR-7 plus TLR-9 attenuates glomerulonephritis and lung injury in experimental lupus. J. Am. Soc. Nephrol.18, 1721–1731 (2007). CASPubMed Google Scholar
Jiang, W., Bhagat, L., Yu, D., Kandimalla, E. R. & Agrawal, S. IMO-3100, an antagonist of Toll-like receptors 7 and 9, modulates gene expression and regulatory networks induced by ligands. J. Immunol.182, 48.25 (2009). Google Scholar
Mullarkey, M. et al. Inhibition of endotoxin response by e5564, a novel Toll-like receptor 4-directed endotoxin antagonist. J. Pharmacol. Exp. Ther.304, 1093–1102 (2003). CASPubMed Google Scholar
Savov, J. D. et al. Toll-like receptor 4 antagonist (E5564) prevents the chronic airway response to inhaled lipopolysaccharide. Am. J. Physiol. Lung Cell. Mol. Physiol.289, L329–L337 (2005). CASPubMed Google Scholar
Czeslick, E., Struppert, A., Simm, A. & Sablotzki, A. E5564 (Eritoran) inhibits lipopolysaccharide-induced cytokine production in human blood monocytes. Inflamm. Res.55, 511–515 (2006). CASPubMed Google Scholar
Bennett-Guerrero, E. et al. A phase II, double-blind, placebo-controlled, ascending-dose study of Eritoran (E5564), a lipid A antagonist, in patients undergoing cardiac surgery with cardiopulmonary bypass. Anesth. Analg.104, 378–383 (2007). CASPubMed Google Scholar
Wasan, K. M. et al. Influence of plasma cholesterol and triglyceride concentrations and eritoran (E5564) micelle size on its plasma pharmacokinetics and ex vivo activity following single intravenous bolus dose into healthy female rabbits. Pharm. Res.25, 176–182 (2008). CASPubMed Google Scholar
Cluff, C. W. et al. Synthetic toll-like receptor 4 agonists stimulate innate resistance to infectious challenge. Infect. Immun.73, 3044–3052 (2005). CASPubMedPubMed Central Google Scholar
Amlie-Lefond, C. et al. Innate immunity for biodefense: a strategy whose time has come. J. Allergy Clin. Immunol.116, 1334–1342 (2005). CASPubMedPubMed Central Google Scholar
Ulevitch, R. J. Therapeutics targeting the innate immune system. Nature Rev. Immunol.4, 512–520 (2004). CAS Google Scholar
Ii, M. et al. A novel cyclohexene derivative, ethyl (6_R_)-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, 1288–1295 (2006). CASPubMed Google Scholar
Ledeboer, A. et al. The glial modulatory drug AV411 attenuates mechanical allodynia in rat models of neuropathic pain. Neuron Glia Biol.2, 279–291 (2006). PubMed Google Scholar
Ledeboer, A., Hutchinson, M. R., Watkins, L. R. & Johnson, K. W. Ibudilast (AV-411). A new class therapeutic candidate for neuropathic pain and opioid withdrawal syndromes. Expert Opin. Investig. Drugs16, 935–950 (2007). CASPubMed Google Scholar
Ungaro, R. et al. A novel toll-like receptor 4 (TLR4) antagonist antibody ameliorates inflammation but impairs mucosal healing in murine colitis. Am. J. Physiol. Gastrointest Liver Physiol.296, G1167–G1179 (2009). CASPubMedPubMed Central Google Scholar
Dunn-Siegrist, I. et al. Pivotal involvement of Fcγ receptor IIA in the neutralization of lipopolysaccharide signaling via a potent novel anti-TLR4 monoclonal antibody 15C1. J. Biol. Chem.282, 34817–34827 (2007). CASPubMed Google Scholar
Chen, K. et al. Toll-like receptors in inflammation, infection and cancer. Int. Immunopharmacol.7, 1271–1285 (2007). CASPubMed Google Scholar
Urbonaviciute, V. et al. Induction of inflammatory and immune responses by HMGB1-nucleosome complexes: implications for the pathogenesis of SLE. J. Exp. Med.205, 3007–3018 (2008). CAS Google Scholar
Arslan, F., de Kleijn, D. P., Timmers, L., Doevendans, P. A. & Pasterkamp, G. Bridging innate immunity and myocardial ischemia/reperfusion injury: the search for therapeutic targets. Curr. Pharm. Des14, 1205–1216 (2008). CASPubMed Google Scholar
Chong, A. J. et al. Toll-like receptor 4 mediates ischemia/reperfusion injury of the heart. J. Thorac. Cardiovasc. Surg.128, 170–179 (2004). CASPubMed Google Scholar
Hua, F. et al. Differential roles of TLR2 and TLR4 in acute focal cerebral ischemia/reperfusion injury in mice. Brain Res.1262, 100–108 (2009). CASPubMedPubMed Central Google Scholar
Tang, S. C. et al. Pivotal role for neuronal Toll-like receptors in ischemic brain injury and functional deficits. Proc. Natl Acad. Sci. USA104, 13798–13803 (2007). CASPubMedPubMed Central Google Scholar
Chang, Y. C., Kao, W. C., Wang, W. Y., Yang, R. B. & Peck, K. Identification and characterization of oligonucleotides that inhibit Toll-like receptor 2-associated immune responses. FASEB J.23, 3078–3088 (2009). This paper shows the development of a novel technique for identifying antagonistic TLR2 aptamers. Functional peptides were identified using a NF-κB reporter assay. One of the identified molecules reduced NF-κB by 80%. CASPubMed Google Scholar
Sheedy, F. J. & O'Neill, L. A. Adding fuel to fire: microRNAs as a new class of mediators of inflammation. Ann. Rheum. Dis.67 (Suppl. 3), 50–55 (2008). Google Scholar
Taganov, K. D., Boldin, M. P., Chang, K. J. & Baltimore, D. NF-κB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc. Natl Acad. Sci. USA103, 12481–12486 (2006). This is the first study to show a miRNA can have a direct role on NF-κB signalling through the targeting of IRAK1 and TRAF6. CASPubMedPubMed Central Google Scholar
O'Connell, R. M., Chaudhuri, A. A., Rao, D. S. & Baltimore, D. Inositol phosphatase SHIP1 is a primary target of miR-155. Proc. Natl Acad. Sci. USA106, 7113–7118 (2009). CASPubMedPubMed Central Google Scholar
Tili, E. et al. Modulation of miR-155 and miR-125b levels following lipopolysaccharide/TNF-α stimulation and their possible roles in regulating the response to endotoxin shock. J. Immunol.179, 5082–5089 (2007). CASPubMed Google Scholar
Harte, M. T. et al. The poxvirus protein A52R targets Toll-like receptor signaling complexes to suppress host defense. J. Exp. Med.197, 343–351 (2003). CASPubMedPubMed Central Google Scholar
McCoy, S. L., Kurtz, S. E., Macarthur, C. J., Trune, D. R. & Hefeneider, S. H. 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, 3006–3014 (2005). CASPubMed Google Scholar
Tsung, A. et al. A novel inhibitory peptide of Toll-like receptor signaling limits lipopolysaccharide-induced production of inflammatory mediators and enhances survival in mice. Shock27, 364–369 (2007). CASPubMed Google Scholar
Buckley, G. M. et al. IRAK-4 inhibitors. Part III: a series of imidazo[1,2-a]pyridines. Bioorg Med. Chem. Lett.18, 3656–3660 (2008). CASPubMed Google Scholar
Cohen, P. Targeting protein kinases for the development of anti-inflammatory drugs. Curr. Opin. Cell Biol.21, 317–324 (2009). CASPubMed Google Scholar
Koziczak-Holbro, M. et al. The critical role of kinase activity of interleukin-1 receptor-associated kinase 4 in animal models of joint inflammation. Arthritis Rheum.60, 1661–1671 (2009). CASPubMed Google Scholar
Kawagoe, T. et al. Sequential control of Toll-like receptor-dependent responses by IRAK1 and IRAK2. Nature Immunol.9, 684–691 (2008). CAS Google Scholar
Nalepa, G., Rolfe, M. & Harper, J. W. Drug discovery in the ubiquitin-proteasome system. Nature Rev. Drug Discov.5, 596–613 (2006). CAS Google Scholar
Guedat, P. & Colland, F. Patented small molecule inhibitors in the ubiquitin proteasome system. BMC Biochem.8 (Suppl. 1), S14 (2007). PubMedPubMed Central Google Scholar
Cossu, F. et al. Structural basis for bivalent smac-mimetics recognition in the IAP protein family. J. Mol. Biol.392, 630–644 (2009). CASPubMed Google Scholar
Cossu, F. et al. Designing Smac-mimetics as antagonists of XIAP, cIAP1, and cIAP2. Biochem. Biophys. Res. Commun.378, 162–167 (2009). CASPubMed Google Scholar
Vince, J. E. et al. IAP antagonists target cIAP1 to induce TNFα-dependent apoptosis. Cell131, 682–693 (2007). One of the first studies to show that IAP antagonists or SMAC mimetics could induce apoptosis of cancer cells by stimulating NF-κB and TNFα. CASPubMed Google Scholar
Vallabhapurapu, S. et al. Nonredundant and complementary functions of TRAF2 and TRAF3 in a ubiquitination cascade that activates NIK-dependent alternative NF-kappaB signaling. Nature Immunol.9, 1364–1370 (2008). This paper describes an alternative NF-κB activation pathway that involves an inhibitor of TLR signalling, TRAF2. CAS Google Scholar
Latz, E. et al. Lipopolysaccharide rapidly traffics to and from the Golgi apparatus with the toll-like receptor 4-MD-2–CD14 complex in a process that is distinct from the initiation of signal transduction. J. Biol. Chem.277, 47834–47843 (2002). CASPubMed Google Scholar
Hughes, A. L. & Piontkivska, H. Functional diversification of the toll-like receptor gene family. Immunogenetics60, 249–256 (2008). CASPubMedPubMed Central Google Scholar
Underhill, D. et al. The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens. Nature401, 811–815 (1999). CASPubMed Google Scholar
Medzhitov, R. & Janeway, C. J. The Toll receptor family and microbial recognition. Trends Microbiol.8, 452–456 (2000). CASPubMed Google Scholar
Muzio, M. et al. Differential expression and regulation of toll-like receptors (TLR) in human leukocytes: selective expression of TLR3 in dendritic cells. J. Immunol.164, 5998–6004 (2000). CASPubMed Google Scholar
Zarember, K. A. & Godowski, P. J. 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, 554–561 (2002). CASPubMed Google Scholar
Strandskog, G., Ellingsen, T. & Jorgensen, J. B. Characterization of three distinct CpG oligonucleotide classes which differ in ability to induce IFN α/β activity and cell proliferation in Atlantic salmon (Salmo salar L.) leukocytes. Dev. Comp. Immunol.31, 39–51 (2007). PubMed Google Scholar
Geddes, K., Magalhaes, J. G. & Girardin, S. E. Unleashing the therapeutic potential of NOD-like receptors. Nature Rev. Drug Discov.8, 465–479 (2009). CAS Google Scholar
Proell, M., Riedl, S. J., Fritz, J. H., Rojas, A. M. & Schwarzenbacher, R. The Nod-like receptor (NLR) family: a tale of similarities and differences. PLoS ONE3, e2119 (2008). PubMedPubMed Central Google Scholar
Fernandes-Alnemri, T., Yu, J. W., Datta, P., Wu, J. & Alnemri, E. S. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature458, 509–513 (2009). CASPubMedPubMed Central Google Scholar
Koizumi, K. et al. Single nucleotide polymorphisms in the gene encoding the major histocompatibility complex class II transactivator (CIITA) in systemic lupus erythematosus. Ann. Rheum. Dis.64, 947–950 (2005). CASPubMedPubMed Central Google Scholar
Macaluso, F. et al. Polymorphisms in NACHT-LRR (NLR) genes in atopic dermatitis. Exp. Dermatol.16, 692–698 (2007). CASPubMed Google Scholar
Magitta, N. F. et al. A coding polymorphism in NALP1 confers risk for autoimmune Addison's disease and type 1 diabetes. Genes Immun.10, 120–124 (2009). CASPubMed Google Scholar
McGovern, D. P. et al. Association between a complex insertion/deletion polymorphism in NOD1 (CARD4) and susceptibility to inflammatory bowel disease. Hum. Mol. Genet.14, 1245–1250 (2005). CASPubMed Google Scholar
Skinningsrud, B. et al. Polymorphisms in CLEC16A and CIITA at 16p13 are associated with primary adrenal insufficiency. J. Clin. Endocrinol. Metab.93, 3310–3317 (2008). CASPubMed Google Scholar
Weidinger, S. et al. Association of NOD1 polymorphisms with atopic eczema and related phenotypes. J. Allergy Clin. Immunol.116, 177–184 (2005). CASPubMed Google Scholar
Noguchi, E., Homma, Y., Kang, X., Netea, M. G. & Ma, X. A Crohn's disease-associated NOD2 mutation suppresses transcription of human IL10 by inhibiting activity of the nuclear ribonucleoprotein hnRNP-A1. Nature Immunol.10, 471–479 (2009). CAS Google Scholar
Ogura, Y. et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature411, 603–606 (2001). CASPubMed Google Scholar
Maksimovic, L. et al. New CIAS1 mutation and anakinra efficacy in overlapping of Muckle-Wells and familial cold autoinflammatory syndromes. Rheumatology47, 309–310 (2008). CASPubMed Google Scholar
Zapata, J. M. et al. Lymphocyte-specific TRAF3 transgenic mice have enhanced humoral responses and develop plasmacytosis, autoimmunity, inflammation, and cancer. Blood113, 4595–4603 (2009). CASPubMedPubMed Central Google Scholar
Bochud, P. Y. et al. Toll-like receptor 2 (TLR2) polymorphisms are associated with reversal reaction in leprosy. J. Infect. Dis.197, 253–261 (2008). CASPubMed Google Scholar
Thuong, N. T. et al. A polymorphism in human TLR2 is associated with increased susceptibility to tuberculous meningitis. Genes Immun.8, 422–428 (2007). CASPubMed Google Scholar
Lorenz, E., Mira, J., Cornish, K., Arbour, N. & Schwartz, D. A novel polymorphism in the toll-like receptor 2 gene and its potential association with staphylococcal infection. Infect. Immun.68, 6398–6401 (2000). CASPubMedPubMed Central Google Scholar
Agnese, D. et al. Human toll-like receptor 4 mutations but not CD14 polymorphisms are associated with an increased risk of Gram-negative infections. J. Infect. Dis.186, 1522–1525 (2002). CASPubMed Google Scholar
Kiechl, S. et al. Toll-like receptor 4 polymorphisms and atherogenesis. N. Engl. J. Med.347, 185–192 (2002). CASPubMed Google Scholar
Sheedy, F. J., Marinou, I., O'Neill, L. A. & Wilson, A. G. The Mal/TIRAP S180L and TLR4 G299D polymorphisms are not associated with susceptibility to, or severity of, rheumatoid arthritis. Ann. Rheum. Dis.67, 1328–1331 (2008). CASPubMed Google Scholar
Gewirtz, A. T. et al. Dominant-negative TLR5 polymorphism reduces adaptive immune response to flagellin and negatively associates with Crohn's disease. Am. J. Physiol. Gastrointest Liver Physiol.290, G1157–G1163 (2006). CASPubMed Google Scholar
Castiblanco, J. et al. TIRAP (MAL) S180L polymorphism is a common protective factor against developing tuberculosis and systemic lupus erythematosus. Infect. Genet. Evol.8, 541–544 (2008). CASPubMed Google Scholar
Khor, C. C. et al. A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis. Nature Genet.39, 523–528 (2007). CASPubMed Google Scholar
Nejentsev, S. et al. Analysis of association of the TIRAP (MAL) S180L variant and tuberculosis in three populations. Nature Genet.40, 261–262; author reply 262–263 (2008). CASPubMed Google Scholar
Ramasawmy, R. et al. Heterozygosity for the S180L variant of MAL/TIRAP, a gene expressing an adaptor protein in the toll-like receptor pathway, is associated with lower risk of developing chronic chagas cardiomyopathy. J. Infect. Dis.199, 1838–1845 (2009). CASPubMed Google Scholar
Ferwerda, B. et al. Functional and genetic evidence that the Mal/TIRAP allele variant 180L has been selected by providing protection against septic shock. Proc. Natl Acad. Sci. USA106, 10272–10277 (2009). CASPubMedPubMed Central Google Scholar
Demirci, F. Y. et al. Association of a common interferon regulatory factor 5 (IRF5) variant with increased risk of systemic lupus erythematosus (SLE). Ann. Hum. Genet.71, 308–311 (2007). CASPubMed Google Scholar
Ferreiro-Neira, I. et al. Opposed independent effects and epistasis in the complex association of IRF5 to SLE. Genes Immun.8, 429–438 (2007). CASPubMed Google Scholar
Tewfik, M. A. et al. Polymorphisms in interleukin-1 receptor-associated kinase 4 are associated with total serum IgE. Allergy64, 746–753 (2009). CASPubMed Google Scholar
Day, N. et al. Interleukin receptor-associated kinase (IRAK-4) deficiency associated with bacterial infections and failure to sustain antibody responses. J. Pediatr.144, 524–526 (2004). PubMed Google Scholar
Picard, C. et al. Pyogenic bacterial infections in humans with IRAK-4 deficiency. Science299, 2076–2079 (2003). CASPubMed Google Scholar
Medvedev, A. E. et al. Distinct mutations in IRAK-4 confer hyporesponsiveness to lipopolysaccharide and interleukin-1 in a patient with recurrent bacterial infections. J. Exp. Med.198, 521–531 (2003). CASPubMedPubMed Central Google Scholar
Picard, C. et al. Inherited human IRAK-4 deficiency: an update. Immunol. Res.38, 347–352 (2007). CASPubMed Google Scholar
Dhiman, N. et al. Associations between SNPs in toll-like receptors and related intracellular signaling molecules and immune responses to measles vaccine: preliminary results. Vaccine26, 1731–1736 (2008). CASPubMedPubMed Central Google Scholar
Sheedy, F. J. et al. Negative regulation of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21. Nature Immunol.11, 141–147 (2010). CAS Google Scholar