臺灣博碩士論文加值系統

NLR家族中的NOD2蛋白是屬於細胞內的受體，可辨識細菌的peptidoglycan所分離的組成份，並且在先天免疫反應裡扮演重要角色。最近一些報導指出，在克隆氏症(Crohn’s disease)的病人中，發現NOD2蛋白的LRR功能區段受到突變，但是NOD2蛋白的功能及調控其訊號傳遞的機制還尚未清楚。在先天免疫系統中，Toll-like receptors (TLRs)是胞漿內模式識別受體家族成員中的一個主要份子，而它的活化反應對於免疫扮演著重要的角色。最近的一些報導提到，TLR4受體在潰瘍性結腸炎(ulcerative colitis)和克隆氏症的病人中有大量表現的情形，也有探討TLR4受體的基因多型性(Asp299Gly and Thr399Ile)與克隆氏症的關係，但是TLR4受體與NOD2蛋白所引起的訊息傳遞之間的分子交互作用關係為何還是相當具有爭議。在此，我們利用研究小鼠的巨噬細胞，在TLR主導的訊息傳導與基因調控的過程，探討NOD2在其中扮演的角色。在小鼠巨噬細胞株(RAW 264.7)，TLR4的專一辨識配體(LPS)可以活化TNFα、IL-1β、iNOS及COX-2的表現，且這些表現會受到NOD2的專一辨識配體(MDP)所加強。另外，我們發現TLR4受體活化會誘發NOD2表現的能力，在RAW巨噬細胞中，我們發現由TLR4受體所主導而活化的MAPK和IKK或IκBα降解過程則不受MDP作用影響，而卻發現MDP作用會對TLR4受體所主導而活化的NF-κB有正向調控。這些結果顯示，NOD2蛋白受到MDP的活化之下，對於TLR4受體所引導的訊息傳遞路徑為一正調控因子。有趣的是，在NOD2蛋白壓抑(NOD2 silencing)的細胞中，LPS所主導活化的發炎反應會更增加並且在LPS耐受機制(LPS tolerance)下也可以誘發發炎反應。因此，我們提出一個論點，在不受MDP刺激之下，NOD2蛋白扮演著一個負向調控TLR4受體所引導的訊息傳遞的角色。此外，我們也證明此負向調控機制是同時需要NOD2蛋白中的CARD和LRR功能區段。在另外的實驗中，我們也發現NOD2蛋白能夠負向調控巨噬細胞的殺菌能力以及TLR4所引發的LC3蛋白的活化(是一個細胞自噬的標誌蛋白)。總括結果，NOD2蛋白對於TLR4受體所引導的訊息傳遞路徑有雙面的調控機制，於是我們提出一個論點﹕在不受配體刺激之下，細胞中持續性表現NOD2蛋白或因細胞受感染而誘發NOD2表現，此情形對於TLR4所引導的訊息傳遞扮演負向調控角色並且正調控TLR4耐受機制以及減少巨噬細胞殺菌能力。儘管NOD2蛋白受到配體而活化能夠增強TLR4所誘發的發炎反應，但如何透過NOD2所引導的雙面調控角色去解釋NOD2參與在克隆氏症的病理機制及過度發炎情形，例如，在克隆氏症的病人中發現NOD2有序列上的突變，但此突變如何導致疾病的形成，仍需要更多的研究。

NOD2 of NLR family has an important role in innate immunity as the cytosolic sensor of microbial components derived from bacterial peptidoglycan. Recent reports indicated that mutations in the leucine-rich repeat (LRR) domain of NOD2 have been implicated in the pathogenesis of Crohn’s disease (CD), yet the function of NOD2 and regulation of the NOD2 pathway remain unclear. Moreover, Toll-like receptor (TLR) is a major family of pattern recognition receptors (PRRs) and plays a crucial role in innate immune system. Recently, TLR4 is strongly up-regulated in both ulcerative colitis and CD. TLR4 polymorphisms (Asp299Gly and Thr399Ile) have been described in CD. Molecular interaction between TLR- and NOD2-signaling pathways is still controversial. Herein, we investigated the role of NOD2 in TLR-mediated signaling and gene regulation in murine macrophages. In murine RAW 264.7 macrophages, MDP (NOD2 ligand) can further increase LPS-induced pro-inflammatory cytokines and mediators, including TNFα, IL-1β, iNOS and COX-2. Accordingly we found the ability of TLR4 to induce NOD2 mRNA expression. We also found that MDP treatment could not affect TLR4-mediated activation of MAPK and IKK or IκBα degradation in RAW 264.7 macrophages, but it could up-regulate NF-κB activation. It is suggested that NOD2 is a positive regulator of TLR4-mediated signaling upon MDP treatment. Interestingly, NOD2 silencing cells lead to a further increase of LPS-induced inflammatory responses, but a decrease of LPS tolerance. We proposed that NOD2 could play an important role in negative regulation of TLR4-mediated signaling pathway in the absence of MDP treatment. Further, we demonstrated that both CARD and LRR domains of NOD2 protein were responsible for negative regulating function of TLR4. Besides, we also found that NOD2 could participate in down-regulation of macrophage bactericidal activity and TLR4-induced LC3 activation (an autophagy marker protein). In summary, NOD2 could have dual effects on TLR4 signaling. We proposed that the constitutively expressed NOD2 or infection up-regulated NOD2 without ligand stimulation plays roles to inhibit TLR4-mediated signaling, increase TLR4 tolerance and decrease bactericidal activity of macrophages. Nevertheless, activated NOD2 upon binding to pathogen-derived ligands can integrate with TLR4 signaling to enhance inflammatory response. How to interpret these two distinct roles together which possibly concomitantly happen in pathogenesis of infectious diseases and control the outcomes of infectious severity, e.g. the development of CD in patients whose NOD2 is functional mutant, still needs more investigation.

Abbreviations.............................................1
Abstract....................................................5
中文摘要...................................................7
Introduction...............................................9
Materials and Methods..............................30
Results....................................................40
Discussion...............................................52
Figures....................................................65
Appendix.................................................85
References..............................................91

Abbott, D.W., Wilkins, A., Asara, J.M., and Cantley, L.C. (2004). The Crohn''s disease protein, NOD2, requires RIP2 in order to induce ubiquitinylation of a novel site on NEMO. Curr Biol 14, 2217-2227.
Abbott, D.W., Yang, Y., Hutti, J.E., Madhavarapu, S., Kelliher, M.A., and Cantley, L.C. (2007). Coordinated regulation of Toll-like receptor and NOD2 signaling by K63-linked polyubiquitin chains. Mol Cell Biol 27, 6012-6025.
Akashi-Takamura, S., and Miyake, K. (2006). Toll-like receptors (TLRs) and immune disorders. J Infect Chemother 12, 233-240.
Akira, S., and Takeda, K. (2004). Toll-like receptor signalling. Nat Rev Immunol 4, 499-511.
Akira, S., Uematsu, S., and Takeuchi, O. (2006). Pathogen recognition and innate immunity. Cell 124, 783-801.
Barnich, N., Hisamatsu, T., Aguirre, J.E., Xavier, R., Reinecker, H.C., and Podolsky, D.K. (2005). GRIM-19 interacts with nucleotide oligomerization domain 2 and serves as downstream effector of anti-bacterial function in intestinal epithelial cells. J Biol Chem 280, 19021-19026.
Bowie, A., and O''Neill, L.A. (2000). The interleukin-1 receptor/Toll-like receptor superfamily: signal generators for pro-inflammatory interleukins and microbial products. J Leukoc Biol 67, 508-514.
Brancho, D., Tanaka, N., Jaeschke, A., Ventura, J.J., Kelkar, N., Tanaka, Y., Kyuuma, M., Takeshita, T., Flavell, R.A., and Davis, R.J. (2003). Mechanism of p38 MAP kinase activation in vivo. Genes Dev 17, 1969-1978.
Chamaillard, M., Hashimoto, M., Horie, Y., Masumoto, J., Qiu, S., Saab, L., Ogura, Y., Kawasaki, A., Fukase, K., Kusumoto, S., Valvano, M.A., Foster, S.J., Mak, T.W., Nunez, G., and Inohara, N. (2003). An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid. Nat Immunol 4, 702-707.
Chen, C.M., Gong, Y., Zhang, M., and Chen, J.J. (2004). Reciprocal cross-talk between Nod2 and TAK1 signaling pathways. J Biol Chem 279, 25876-25882.
Chen, Z., Gibson, T.B., Robinson, F., Silvestro, L., Pearson, G., Xu, B., Wright, A., Vanderbilt, C., and Cobb, M.H. (2001). MAP kinases. Chem Rev 101, 2449-2476.
Chen, Z.J. (2005). Ubiquitin signalling in the NF-kappaB pathway. Nat Cell Biol 7, 758-765.
Cho, J.H. (2008). The genetics and immunopathogenesis of inflammatory bowel disease. Nat Rev Immunol 8, 458-466.
Cusson-Hermance, N., Khurana, S., Lee, T.H., Fitzgerald, K.A., and Kelliher, M.A. (2005). Rip1 mediates the Trif-dependent toll-like receptor 3- and 4-induced NF-{kappa}B activation but does not contribute to interferon regulatory factor 3 activation. J Biol Chem 280, 36560-36566.
Damiano, J.S., Oliveira, V., Welsh, K., and Reed, J.C. (2004). Heterotypic interactions among NACHT domains: implications for regulation of innate immune responses. Biochem J 381, 213-219.
Duncan, J.A., Bergstralh, D.T., Wang, Y., Willingham, S.B., Ye, Z., Zimmermann, A.G., and Ting, J.P. (2007). Cryopyrin/NALP3 binds ATP/dATP, is an ATPase, and requires ATP binding to mediate inflammatory signaling. Proc Natl Acad Sci U S A 104, 8041-8046.
Eckmann, L., and Karin, M. (2005). NOD2 and Crohn''s disease: loss or gain of function? Immunity 22, 661-667.
Faustin, B., Lartigue, L., Bruey, J.M., Luciano, F., Sergienko, E., Bailly-Maitre, B., Volkmann, N., Hanein, D., Rouiller, I., and Reed, J.C. (2007). Reconstituted NALP1 inflammasome reveals two-step mechanism of caspase-1 activation. Mol Cell 25, 713-724.
Fisher, S.A., Tremelling, M., Anderson, C.A., Gwilliam, R., Bumpstead, S., Prescott, N.J., Nimmo, E.R., Massey, D., Berzuini, C., Johnson, C., Barrett, J.C., Cummings, F.R., Drummond, H., Lees, C.W., Onnie, C.M., Hanson, C.E., Blaszczyk, K., Inouye, M., Ewels, P., Ravindrarajah, R., Keniry, A., Hunt, S., Carter, M., Watkins, N., Ouwehand, W., Lewis, C.M., Cardon, L., Lobo, A., Forbes, A., Sanderson, J., Jewell, D.P., Mansfield, J.C., Deloukas, P., Mathew, C.G., Parkes, M., and Satsangi, J. (2008). Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn''s disease. Nat Genet 40, 710-712.
Foster, S.L., Hargreaves, D.C., and Medzhitov, R. (2007). Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature 447, 972-978.
Fritz, J.H., Ferrero, R.L., Philpott, D.J., and Girardin, S.E. (2006). Nod-like proteins in immunity, inflammation and disease. Nat Immunol 7, 1250-1257.
Fritz, J.H., Girardin, S.E., Fitting, C., Werts, C., Mengin-Lecreulx, D., Caroff, M., Cavaillon, J.M., Philpott, D.J., and Adib-Conquy, M. (2005). Synergistic stimulation of human monocytes and dendritic cells by Toll-like receptor 4 and NOD1- and NOD2-activating agonists. Eur J Immunol 35, 2459-2470.
Girardin, S.E., Boneca, I.G., Carneiro, L.A., Antignac, A., Jehanno, M., Viala, J., Tedin, K., Taha, M.K., Labigne, A., Zahringer, U., Coyle, A.J., DiStefano, P.S., Bertin, J., Sansonetti, P.J., and Philpott, D.J. (2003a). Nod1 detects a unique muropeptide from gram-negative bacterial peptidoglycan. Science 300, 1584-1587.
Girardin, S.E., Boneca, I.G., Viala, J., Chamaillard, M., Labigne, A., Thomas, G., Philpott, D.J., and Sansonetti, P.J. (2003b). Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem 278, 8869-8872.
Girardin, S.E., Tournebize, R., Mavris, M., Page, A.L., Li, X., Stark, G.R., Bertin, J., DiStefano, P.S., Yaniv, M., Sansonetti, P.J., and Philpott, D.J. (2001). CARD4/Nod1 mediates NF-kappaB and JNK activation by invasive Shigella flexneri. EMBO Rep 2, 736-742.
Grant, S.F., Baldassano, R.N., and Hakonarson, H. (2008). Classification of genetic profiles of Crohn''s disease: a focus on the ATG16L1 gene. Expert Rev Mol Diagn 8, 199-207.
Gutierrez, M.G., Master, S.S., Singh, S.B., Taylor, G.A., Colombo, M.I., and Deretic, V. (2004). Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 119, 753-766.
Gutierrez, O., Pipaon, C., Inohara, N., Fontalba, A., Ogura, Y., Prosper, F., Nunez, G., and Fernandez-Luna, J.L. (2002). Induction of Nod2 in myelomonocytic and intestinal epithelial cells via nuclear factor-kappa B activation. J Biol Chem 277, 41701-41705.
Hacker, H., and Karin, M. (2006). Regulation and function of IKK and IKK-related kinases. Sci STKE 2006, re13.
Hacker, H., Redecke, V., Blagoev, B., Kratchmarova, I., Hsu, L.C., Wang, G.G., Kamps, M.P., Raz, E., Wagner, H., Hacker, G., Mann, M., and Karin, M. (2006). Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6. Nature 439, 204-207.
Hacker, H., Vabulas, R.M., Takeuchi, O., Hoshino, K., Akira, S., and Wagner, H. (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.
Hampe, J., Franke, A., Rosenstiel, P., Till, A., Teuber, M., Huse, K., Albrecht, M., Mayr, G., De La Vega, F.M., Briggs, J., Gunther, S., Prescott, N.J., Onnie, C.M., Hasler, R., Sipos, B., Folsch, U.R., Lengauer, T., Platzer, M., Mathew, C.G., Krawczak, M., and Schreiber, S. (2007). A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet 39, 207-211.
Harton, J.A., Linhoff, M.W., Zhang, J., and Ting, J.P. (2002). Cutting edge: CATERPILLER: a large family of mammalian genes containing CARD, pyrin, nucleotide-binding, and leucine-rich repeat domains. J Immunol 169, 4088-4093.
Hasegawa, M., Fujimoto, Y., Lucas, P.C., Nakano, H., Fukase, K., Nunez, G., and Inohara, N. (2008). A critical role of RICK/RIP2 polyubiquitination in Nod-induced NF-kappaB activation. EMBO J 27, 373-383.
Hasegawa, M., Yang, K., Hashimoto, M., Park, J.H., Kim, Y.G., Fujimoto, Y., Nunez, G., Fukase, K., and Inohara, N. (2006). Differential release and distribution of Nod1 and Nod2 immunostimulatory molecules among bacterial species and environments. J Biol Chem 281, 29054-29063.
Hayashi, F., Smith, K.D., Ozinsky, A., Hawn, T.R., Yi, E.C., Goodlett, D.R., Eng, J.K., Akira, S., Underhill, D.M., and Aderem, A. (2001). The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 410, 1099-1103.
Hedl, M., Li, J., Cho, J.H., and Abraham, C. (2007). Chronic stimulation of Nod2 mediates tolerance to bacterial products. Proc Natl Acad Sci U S A 104, 19440-19445.
Hemmi, H., Kaisho, T., Takeuchi, O., Sato, S., Sanjo, H., Hoshino, K., Horiuchi, T., Tomizawa, H., Takeda, K., and Akira, S. (2002). Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol 3, 196-200.
Hisamatsu, T., Suzuki, M., and Podolsky, D.K. (2003). Interferon-gamma augments CARD4/NOD1 gene and protein expression through interferon regulatory factor-1 in intestinal epithelial cells. J Biol Chem 278, 32962-32968.
Hoebe, K., and Beutler, B. (2006). TRAF3: a new component of the TLR-signaling apparatus. Trends Mol Med 12, 187-189.
Hoebe, K., Du, X., Georgel, P., Janssen, E., Tabeta, K., Kim, S.O., Goode, J., Lin, P., Mann, N., Mudd, S., Crozat, K., Sovath, S., Han, J., and Beutler, B. (2003). Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature 424, 743-748.
Hommes, D., van den Blink, B., Plasse, T., Bartelsman, J., Xu, C., Macpherson, B., Tytgat, G., Peppelenbosch, M., and Van Deventer, S. (2002). Inhibition of stress-activated MAP kinases induces clinical improvement in moderate to severe Crohn''s disease. Gastroenterology 122, 7-14.
Hsu, L.C., Ali, S.R., McGillivray, S., Tseng, P.H., Mariathasan, S., Humke, E.W., Eckmann, L., Powell, J.J., Nizet, V., Dixit, V.M., and Karin, M. (2008). A NOD2-NALP1 complex mediates caspase-1-dependent IL-1beta secretion in response to Bacillus anthracis infection and muramyl dipeptide. Proc Natl Acad Sci U S A 105, 7803-7808.
Hsu, Y.M., Zhang, Y., You, Y., Wang, D., Li, H., Duramad, O., Qin, X.F., Dong, C., and Lin, X. (2007). The adaptor protein CARD9 is required for innate immune responses to intracellular pathogens. Nat Immunol 8, 198-205.
Hugot, J.P., Chamaillard, M., Zouali, H., Lesage, S., Cezard, J.P., Belaiche, J., Almer, S., Tysk, C., O''Morain, C.A., Gassull, M., Binder, V., Finkel, Y., Cortot, A., Modigliani, R., Laurent-Puig, P., Gower-Rousseau, C., Macry, J., Colombel, J.F., Sahbatou, M., and Thomas, G. (2001). Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn''s disease. Nature 411, 599-603.
Inohara, Chamaillard, McDonald, C., and Nunez, G. (2005). NOD-LRR proteins: role in host-microbial interactions and inflammatory disease. Annu Rev Biochem 74, 355-383.
Inohara, N., Koseki, T., del Peso, L., Hu, Y., Yee, C., Chen, S., Carrio, R., Merino, J., Liu, D., Ni, J., and Nunez, G. (1999). Nod1, an Apaf-1-like activator of caspase-9 and nuclear factor-kappaB. J Biol Chem 274, 14560-14567.
Inohara, N., and Nunez, G. (2001). The NOD: a signaling module that regulates apoptosis and host defense against pathogens. Oncogene 20, 6473-6481.
Inohara, N., and Nunez, G. (2003). NODs: intracellular proteins involved in inflammation and apoptosis. Nat Rev Immunol 3, 371-382.
Inohara, N., Ogura, Y., Fontalba, A., Gutierrez, O., Pons, F., Crespo, J., Fukase, K., Inamura, S., Kusumoto, S., Hashimoto, M., Foster, S.J., Moran, A.P., Fernandez-Luna, J.L., and Nunez, G. (2003). Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn''s disease. J Biol Chem 278, 5509-5512.
Janeway, C.A., Jr., and Medzhitov, R. (2002). Innate immune recognition. Annu Rev Immunol 20, 197-216.
Kanneganti, T.D., Lamkanfi, M., and Nunez, G. (2007). Intracellular NOD-like receptors in host defense and disease. Immunity 27, 549-559.
Karin, M., and Greten, F.R. (2005). NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol 5, 749-759.
Kawai, T., Adachi, O., Ogawa, T., Takeda, K., and Akira, S. (1999). Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 11, 115-122.
Kawai, T., and Akira, S. (2006). TLR signaling. Cell Death Differ 13, 816-825.
Kawai, T., Takeuchi, O., Fujita, T., Inoue, J., Muhlradt, P.F., Sato, S., Hoshino, K., and Akira, S. (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, 5887-5894.
Kim, Y.G., Park, J.H., Shaw, M.H., Franchi, L., Inohara, N., and Nunez, G. (2008). The cytosolic sensors Nod1 and Nod2 are critical for bacterial recognition and host defense after exposure to Toll-like receptor ligands. Immunity 28, 246-257.
King, K., Bagnall, R., Fisher, S.A., Sheikh, F., Cuthbert, A., Tan, S., Mundy, N.I., Rosenstiel, P., Schreiber, S., Mathew, C.G., and Roberts, R.G. (2007). Identification, evolution, and association study of a novel promoter and first exon of the human NOD2 (CARD15) gene. Genomics 90, 493-501.
Kirkegaard, K., Taylor, M.P., and Jackson, W.T. (2004). Cellular autophagy: surrender, avoidance and subversion by microorganisms. Nat Rev Microbiol 2, 301-314.
Kobayashi, K., Inohara, N., Hernandez, L.D., Galan, J.E., Nunez, G., Janeway, C.A., Medzhitov, R., and Flavell, R.A. (2002). RICK/Rip2/CARDIAK mediates signalling for receptors of the innate and adaptive immune systems. Nature 416, 194-199.
Kobayashi, K.S., Chamaillard, M., Ogura, Y., Henegariu, O., Inohara, N., Nunez, G., and Flavell, R.A. (2005). Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 307, 731-734.
Kopp, E., and Medzhitov, R. (2003). Recognition of microbial infection by Toll-like receptors. Curr Opin Immunol 15, 396-401.
Kyriakis, J.M., and Avruch, J. (2001). Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev 81, 807-869.
LeBlanc, P.M., Yeretssian, G., Rutherford, N., Doiron, K., Nadiri, A., Zhu, L., Green, D.R., Gruenheid, S., and Saleh, M. (2008). Caspase-12 modulates NOD signaling and regulates antimicrobial peptide production and mucosal immunity. Cell Host Microbe 3, 146-157.
Lee, M.S., and Kim, Y.J. (2007). Pattern-recognition receptor signaling initiated from extracellular, membrane, and cytoplasmic space. Mol Cells 23, 1-10.
Levine, B., and Deretic, V. (2007). Unveiling the roles of autophagy in innate and adaptive immunity. Nat Rev Immunol 7, 767-777.
Liew, F.Y., Xu, D., Brint, E.K., and O''Neill, L.A. (2005). Negative regulation of toll-like receptor-mediated immune responses. Nat Rev Immunol 5, 446-458.
Liu, Y., Shepherd, E.G., and Nelin, L.D. (2007). MAPK phosphatases--regulating the immune response. Nat Rev Immunol 7, 202-212.
Loiarro, M., Capolunghi, F., Fanto, N., Gallo, G., Campo, S., Arseni, B., Carsetti, R., Carminati, P., De Santis, R., Ruggiero, V., and Sette, C. (2007). Pivotal Advance: Inhibition of MyD88 dimerization and recruitment of IRAK1 and IRAK4 by a novel peptidomimetic compound. J Leukoc Biol 82, 801-810.
Maeda, S., Hsu, L.C., Liu, H., Bankston, L.A., Iimura, M., Kagnoff, M.F., Eckmann, L., and Karin, M. (2005). Nod2 mutation in Crohn''s disease potentiates NF-kappaB activity and IL-1beta processing. Science 307, 734-738.
Marina-Garcia, N., Franchi, L., Kim, Y.G., Miller, D., McDonald, C., Boons, G.J., and Nunez, G. (2008). Pannexin-1-mediated intracellular delivery of muramyl dipeptide induces caspase-1 activation via cryopyrin/NLRP3 independently of Nod2. J Immunol 180, 4050-4057.
Martinon, F., Agostini, L., Meylan, E., and Tschopp, J. (2004). Identification of bacterial muramyl dipeptide as activator of the NALP3/cryopyrin inflammasome. Curr Biol 14, 1929-1934.
McGovern, D.P., Hysi, P., Ahmad, T., van Heel, D.A., Moffatt, M.F., Carey, A., Cookson, W.O., and Jewell, D.P. (2005). Association between a complex insertion/deletion polymorphism in NOD1 (CARD4) and susceptibility to inflammatory bowel disease. Hum Mol Genet 14, 1245-1250.
Medvedev, A.E., Piao, W., Shoenfelt, J., Rhee, S.H., Chen, H., Basu, S., Wahl, L.M., Fenton, M.J., and Vogel, S.N. (2007). Role of TLR4 tyrosine phosphorylation in signal transduction and endotoxin tolerance. J Biol Chem 282, 16042-16053.
Meier, R., Rouse, J., Cuenda, A., Nebreda, A.R., and Cohen, P. (1996). Cellular stresses and cytokines activate multiple mitogen-activated-protein kinase kinase homologues in PC12 and KB cells. Eur J Biochem 236, 796-805.
Meylan, E., Burns, K., Hofmann, K., Blancheteau, V., Martinon, F., Kelliher, M., and Tschopp, J. (2004). RIP1 is an essential mediator of Toll-like receptor 3-induced NF-kappa B activation. Nat Immunol 5, 503-507.
Nakagawa, I., Amano, A., Mizushima, N., Yamamoto, A., Yamaguchi, H., Kamimoto, T., Nara, A., Funao, J., Nakata, M., Tsuda, K., Hamada, S., and Yoshimori, T. (2004). Autophagy defends cells against invading group A Streptococcus. Science 306, 1037-1040.
Netea, M.G., Ferwerda, G., de Jong, D.J., Jansen, T., Jacobs, L., Kramer, M., Naber, T.H., Drenth, J.P., Girardin, S.E., Kullberg, B.J., Adema, G.J., and Van der Meer, J.W. (2005). Nucleotide-binding oligomerization domain-2 modulates specific TLR pathways for the induction of cytokine release. J Immunol 174, 6518-6523.
O''Neill, L.A., and Bowie, A.G. (2007). The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol 7, 353-364.
Oganesyan, G., Saha, S.K., Guo, B., He, J.Q., Shahangian, A., Zarnegar, B., Perry, A., and Cheng, G. (2006). Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response. Nature 439, 208-211.
Ogawa, M., Yoshimori, T., Suzuki, T., Sagara, H., Mizushima, N., and Sasakawa, C. (2005). Escape of intracellular Shigella from autophagy. Science 307, 727-731.
Ogura, Y., Bonen, D.K., Inohara, N., Nicolae, D.L., Chen, F.F., Ramos, R., Britton, H., Moran, T., Karaliuskas, R., Duerr, R.H., Achkar, J.P., Brant, S.R., Bayless, T.M., Kirschner, B.S., Hanauer, S.B., Nunez, G., and Cho, J.H. (2001a). A frameshift mutation in NOD2 associated with susceptibility to Crohn''s disease. Nature 411, 603-606.
Ogura, Y., Inohara, N., Benito, A., Chen, F.F., Yamaoka, S., and Nunez, G. (2001b). Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB. J Biol Chem 276, 4812-4818.
Ono, K., and Han, J. (2000). The p38 signal transduction pathway: activation and function. Cell Signal 12, 1-13.
Oshiumi, H., Matsumoto, M., Funami, K., Akazawa, T., and Seya, T. (2003). TICAM-1, an adaptor molecule that participates in Toll-like receptor 3-mediated interferon-beta induction. Nat Immunol 4, 161-167.
Park, J.H., Kim, Y.G., McDonald, C., Kanneganti, T.D., Hasegawa, M., Body-Malapel, M., Inohara, N., and Nunez, G. (2007). RICK/RIP2 mediates innate immune responses induced through Nod1 and Nod2 but not TLRs. J Immunol 178, 2380-2386.
Pauleau, A.L., and Murray, P.J. (2003). Role of nod2 in the response of macrophages to toll-like receptor agonists. Mol Cell Biol 23, 7531-7539.
Prescott, N.J., Fisher, S.A., Franke, A., Hampe, J., Onnie, C.M., Soars, D., Bagnall, R., Mirza, M.M., Sanderson, J., Forbes, A., Mansfield, J.C., Lewis, C.M., Schreiber, S., and Mathew, C.G. (2007). A nonsynonymous SNP in ATG16L1 predisposes to ileal Crohn''s disease and is independent of CARD15 and IBD5. Gastroenterology 132, 1665-1671.
Rosenstiel, P., Fantini, M., Brautigam, K., Kuhbacher, T., Waetzig, G.H., Seegert, D., and Schreiber, S. (2003). TNF-alpha and IFN-gamma regulate the expression of the NOD2 (CARD15) gene in human intestinal epithelial cells. Gastroenterology 124, 1001-1009.
Roux, P.P., and Blenis, J. (2004). ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions. Microbiol Mol Biol Rev 68, 320-344.
Rubinsztein, D.C., Gestwicki, J.E., Murphy, L.O., and Klionsky, D.J. (2007). Potential therapeutic applications of autophagy. Nat Rev Drug Discov 6, 304-312.
Sanjuan, M.A., Dillon, C.P., Tait, S.W., Moshiach, S., Dorsey, F., Connell, S., Komatsu, M., Tanaka, K., Cleveland, J.L., Withoff, S., and Green, D.R. (2007). Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis. Nature 450, 1253-1257.
Sato, S., Sugiyama, M., Yamamoto, M., Watanabe, Y., Kawai, T., Takeda, K., and Akira, S. (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, 4304-4310.
Schnare, M., Holt, A.C., Takeda, K., Akira, S., and Medzhitov, R. (2000). Recognition of CpG DNA is mediated by signaling pathways dependent on the adaptor protein MyD88. Curr Biol 10, 1139-1142.
Schorey, J.S., and Cooper, A.M. (2003). Macrophage signalling upon mycobacterial infection: the MAP kinases lead the way. Cell Microbiol 5, 133-142.
Singh, S.B., Davis, A.S., Taylor, G.A., and Deretic, V. (2006). Human IRGM induces autophagy to eliminate intracellular mycobacteria. Science 313, 1438-1441.
Stehlik, C., Hayashi, H., Pio, F., Godzik, A., and Reed, J.C. (2003). CARD6 is a modulator of NF-kappa B activation by Nod1- and Cardiak-mediated pathways. J Biol Chem 278, 31941-31949.
Strober, W., Murray, P.J., Kitani, A., and Watanabe, T. (2006). Signalling pathways and molecular interactions of NOD1 and NOD2. Nat Rev Immunol 6, 9-20.
Tada, H., Aiba, S., Shibata, K., Ohteki, T., and Takada, H. (2005). 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 73, 7967-7976.
Takahashi, Y., Isuzugawa, K., Murase, Y., Imai, M., Yamamoto, S., Iizuka, M., Akira, S., Bahr, G.M., Momotani, E., Hori, M., Ozaki, H., and Imakawa, K. (2006). Up-regulation of NOD1 and NOD2 through TLR4 and TNF-alpha in LPS-treated murine macrophages. J Vet Med Sci 68, 471-478.
Takeda, K., and Akira, S. (2005). Toll-like receptors in innate immunity. Int Immunol 17, 1-14.
Uehara, A., and Takada, H. (2007). Functional TLRs and NODs in human gingival fibroblasts. J Dent Res 86, 249-254.
Uehara, A., Yang, S., Fujimoto, Y., Fukase, K., Kusumoto, S., Shibata, K., Sugawara, S., and Takada, H. (2005). 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 7, 53-61.
Uehori, J., Fukase, K., Akazawa, T., Uematsu, S., Akira, S., Funami, K., Shingai, M., Matsumoto, M., Azuma, I., Toyoshima, K., Kusumoto, S., and Seya, T. (2005). Dendritic cell maturation induced by muramyl dipeptide (MDP) derivatives: monoacylated MDP confers TLR2/TLR4 activation. J Immunol 174, 7096-7103.
Underhill, D.M., and Ozinsky, A. (2002). Phagocytosis of microbes: complexity in action. Annu Rev Immunol 20, 825-852.
van Heel, D.A., Ghosh, S., Hunt, K.A., Mathew, C.G., Forbes, A., Jewell, D.P., and Playford, R.J. (2005). Synergy between TLR9 and NOD2 innate immune responses is lost in genetic Crohn''s disease. Gut 54, 1553-1557.
Watanabe, T., Kitani, A., Murray, P.J., and Strober, W. (2004). NOD2 is a negative regulator of Toll-like receptor 2-mediated T helper type 1 responses. Nat Immunol 5, 800-808.
Weston, C.R., and Davis, R.J. (2002). The JNK signal transduction pathway. Curr Opin Genet Dev 12, 14-21.
Wolfert, M.A., Murray, T.F., Boons, G.J., and Moore, J.N. (2002). The origin of the synergistic effect of muramyl dipeptide with endotoxin and peptidoglycan. J Biol Chem 277, 39179-39186.
Xu, Y., Jagannath, C., Liu, X.D., Sharafkhaneh, A., Kolodziejska, K.E., and Eissa, N.T. (2007). Toll-like receptor 4 is a sensor for autophagy associated with innate immunity. Immunity 27, 135-144.
Yamamoto, M., Sato, S., Hemmi, H., Hoshino, K., Kaisho, T., Sanjo, H., Takeuchi, O., Sugiyama, M., Okabe, M., Takeda, K., and Akira, S. (2003). Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science 301, 640-643.
Yamamoto, M., Sato, S., Hemmi, H., Sanjo, H., Uematsu, S., Kaisho, T., Hoshino, K., Takeuchi, O., Kobayashi, M., Fujita, T., Takeda, K., and Akira, S. (2002). Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4. Nature 420, 324-329.
Yang, S., Tamai, R., Akashi, S., Takeuchi, O., Akira, S., Sugawara, S., and Takada, H. (2001). Synergistic effect of muramyldipeptide with lipopolysaccharide or lipoteichoic acid to induce inflammatory cytokines in human monocytic cells in culture. Infect Immun 69, 2045-2053.
Yang, Y., Yin, C., Pandey, A., Abbott, D., Sassetti, C., and Kelliher, M.A. (2007). NOD2 pathway activation by MDP or Mycobacterium tuberculosis infection involves the stable polyubiquitination of Rip2. J Biol Chem 282, 36223-36229.
Zhou, H., Wertz, I., O''Rourke, K., Ultsch, M., Seshagiri, S., Eby, M., Xiao, W., and Dixit, V.M. (2004). Bcl10 activates the NF-kappaB pathway through ubiquitination of NEMO. Nature 427, 167-171.