摘要
IL-1R是TIR超家族成员,在IL-1、LPS介导的NF-kB信号通路中发挥重要作用。本文利用生物信息学和分子克隆等技术从模式鱼类中鉴定出鱼类IL-1RI、 DIGIRR、SIGIRR基因,并对它们的蛋白结构、遗传进化及免疫学功能进行了研究。
论文第一部分首次从Tetraodon nigroviridis鉴定出IL-1RI受体、对其基因结构、蛋白特征、组织分布、基因功能等进行了初步研究。构建原核表达质粒,纯化IL-1RI蛋白、制备了多克隆抗体。ELISA实验证明IL-1RI胞外区三个免疫球蛋白能够结合配体分子IL-1β,与IL-1RI、IL-1协同进化的计算结果相对应。而且抗体封闭IL-1RI后,IL-1介导的免疫反应被显著抑制。论文第二部分首次从模式鱼类Tetraodon nigroviridis、Gasterosteus aculeatus、Takifugu rubripe、 Oryzias latipes中鉴定出DIGIRR基因,是IL-1R/TLR家族的一个新成员。与其它IL-1R受体不同的是,DIGIRR具有两个免疫球蛋白、一个Arg-Tyr突变的TIR结构域、以及高尔基体亚细胞定位的特征。LPS刺激后,DIGIRR的mRNA表达量显著升高。体外实验表明,DIGIRR能够显著抑制IL-1β、LPS介导的NF-kB信号。而且体内DIGIRR被siRNA抑制后,IL-1β诱导的炎症因子表达量显著上调,这些数据充分证明了DIGIRR在IL-1、LPS介导的炎症信号通路中是一个负调节因子。论文第三部分首次鉴定出鱼类SIGIRR分子,蛋白结构分析、基因功能实验等方面都证实了克隆得到的受体分子是哺乳动物SIGIRR的同系物,斑马鱼SIGIRR能够抑制IL-1、LPS、CpG介导的NF-kB信号通路。
在进化上,本文提出一个IL-1RI、DIGIRR、SIGIRR起源与进化的假说,DIGIRR是SIGIRR、IL-1RI之间过渡类型的分子。DIGIRR、SIGIRR起源于同一个祖先分子IL-1R,经过两次基因复制事件,祖先分子IL-1R演化成了DIGIRR,随着世系分离,一部分物种保留了DIGIRR,而其它物种的DIGIRR进化成了SIGIRR。鱼类IL-1RI、DIGIRR、SIGIRR的鉴定证实了低等脊椎动物鱼类IL-1R/TLR调控机制的存在,有助于更好地理解IL-1R/TLR调控网络的进化历程,为鱼类免疫、病害防治工作提供了有利资料和科学依据。
Interleukin-1receptors belong to the TIR (IL-1R/TLR) superfamily members that play crucial roles in IL-1-and LPS-mediated NF-κB signaling pathways. In this study, IL-1RI, DIGIRR and SIGIRR were predicted and isolated from teleosts by bioinformatics and molecular cloning. Moreover, the protein characterization, molecular evolution and immune functions were further studied.
In part one, IL-1RI was first cloned from Tetraodon nigroviridis, and then we performed analysis of gene structures, protein characterization, mRNA distribution and gene functions. Recombinant protein of IL-1RI was successfully purified and obtained by prokaryotic expression system, and whereafter the polyclonal antibody was preapared based on the purified IL-1RI. The data showed that IL-1R receptor had affinities with its ligands IL-1β in a dose-dependent manner by ELISA, in agreement with the results of co-evolution relationship between IL-1RI and IL-1. Moreover, when IL-1RI was blocked by the anti-IL-1RI antibodies, the relative gene expression level of IL-1β-incued inflamatory factors were significant reduced.
In part two, we report a novel double-Ig-IL-1R related molecule (DIGIRR) from four model fish(Tetraodon nigroviridis, Gasterosteus aculeatus, Takifugu rubripes and Oryzias latipes), adding a previously unknown homologue to the TLR-IL-1R family. This DIGIRR molecule contains two Ig-like domains in the extracellular region, one Arg-Tyr-mutated TIR domain in the intracellular region, and a unique subcellular localization within the Golgi apparatus. These characteristics distinguish DIGIRR from other known family members. The expression of DIGIRR was significantly induced by LPS-stimulation. In vitro injection of DIGIRR into zebrafish embryos dramatically inhibited LPS-and IL-1β-induced NF-κB activation. Moreover, in vivo knockdown of DIGIRR by siRNA significantly promoted the expression of IL-1β-stimulated pro-inflammatory cytokines (IL-6and IL-1β) in DIGIRR-silenced liver and kidney tissues, and in leucocytes. These results strongly suggest that DIGIRR is an important negative regulator of LPS-and IL-1β-mediated signaling pathways and inflammatory responses.
In part three, SIGIRR was first isolated from teleost zebrafish, which is considered as the homologue of mammalians SIGIRR according to the analysis of protein characterizations and the results of gene functions. Zebrafish SIGIRR was able to inhibit IL-1β-,LPS-and CpG-indued NF-kB signaling pathways.
Evolutionally, we propose a hypothesis that DIGIRR might be an evolutionary "transitional molecule" between IL-1R and SIGIRR, representing a shift from a potent receptor to a negative regulator. These three molecules probably originated from a common ancient IL-1R-like molecule. Following two rounds of genome dulplications, ancient IL-1R-like molecule evolved into DIGIRR. With lineage divergence, parts of specieses retained DIGIRR, and meanwhile DIGIRR became SIGIRR in the other specieses.
The identifications of IL-1RI, DIGIRR and SIGIRR demonstrat that there exsit the regulation mechanisms of IL-1R/TLR signal pathways in teleosts. All data not only contribute to better understand the evolutionary history of NF-kB signaling patyways, but also provide available data and scientific evidence for host immune and disease control in fish.
引文
1. Dinarello, C.A., Thermoregulation and the pathogenesis of fever. Infect Dis Clin North Am, 1996.10(2):p.433-49.
2. Sims, J.E. and D.E. Smith, The IL-1 family:regulators of immunity. Nature Reviews Immunology,2010.10(2):p.89-102.
3. Bowie, A. and L.A. O'Neill, The interleukin-1 receptor/Toll-like receptor superfamily:signal generators for pro-inflammatory interleukins and microbial products. J Leukoc Biol,2000. 67(4):p.508-14.
4. Mitcham, J.L., et al., T1/ST2 signaling establishes it as a member of an expanding interleukin-1 receptor family, J Biol Chem,1996.271(10):p.5777-83.
5. O'Neill, L.A., The interleukin-1 receptor/Toll-like receptor superfamily:10 years of progress. Immunol Rev,2008.226:p.10-8.
6. Takeda, K., T. Kaisho, and S. Akira, Toll-like receptors. Annu Rev Immunol,2003.21:p. 335-76.
7. Medzhitov, R., Toll-like receptors and innate immunity. Nat Rev Immunol,2001.1(2):p. 135-45.
8. Rock, F.L., et al., A family of human receptors structurally related to Drosophila Toll. Proc Natl Acad Sci U S A,1998.95(2):p.588-93.
9. Stock, J. and M. Levit, Signal transduction:hair brains in bacterial chemotaxis. Curr Biol, 2000.10(1):p. R11-4.
10. Xu, Y, et al., Structural basis for signal transduction by the Toll'interleukin-1 receptor domains. Nature,2000.408(6808):p.111-5.
11. Burns, K., et al., MyD88, an adapter protein involved in interleukin-1 signaling. J Biol Chem, 1998.273(20):p.12203-9.
12. Wesche, H., et al., MyD88:an adapter that recruits IRAK to the IL-1 receptor complex. Immunity,1997.7(6):p.837-47.
13. O'Neill, L.A. and C.A. Dinarello, The IL-1 receptor/toll-like receptor superfamily:crucial receptors for inflammation and host defense. Immunol Today,2000.21(5):p.206-9.
14. Heguy, A., et al., Amino-Acids Conserved in Interleukin-1 Receptors (Il-Irs) and the Drosophila Toll Protein Are Essential for Il-lr Signal Transduction. Journal of Biological Chemistry,1992.267(4):p.2605-2609.
15. Poltorak, A., et al., Defective LPS signaling in C3H/HeJand C57BL/10ScCr mice:mutations in Tlr4gene. Science,1998.282(5396):p.2085-8.
16. Slack, J.L., et al., Identification of two major sites in the type 1 interleukin-1 receptor cytoplasmic region responsible for coupling to pro-inflammatory signaling pathways. J Biol Chem,2000.275(7):p.4670-8.
17. Radons, J., et al., Identification of essential regions in the cytoplasmic tail of interleukin-1 receptor accessory protein critical for interleukin-1 signaling. J Biol Chem,2002.277(19):p. 16456-63.
18. Kuno, K., et al., Structure and function of the intracellular portion of the mouse interleukin 1 receptor (type 1). Determining the essential region for transducing signals to activate the interleukin 8 gene. J Biol Chem,1993.268(18):p.13510-8.
19. Croston, G.E., Z. Cao, and D.V. Goeddel, NF-kappa B activation by interleukin-1 (IL-1) requires an IL-1 receptor-associated protein kinase activity. J Biol Chem,1995.270(28):p. 16514-7.
20. Du, X., et al., Three novel mammalian toll-like receptors:gene structure, expression, and evolution. Eur Cytokine Netw,2000.11(3):p.362-71.
21. Sims, J.E., et al., cDNA expression cloning of the IL-1 receptor, a member of the immunoglobulin superfamily. Science,1988.241(4865):p.585-9.
22. Sims, J.E., et al., Cloning the interleukin 1 receptor from human T cells. Proc Natl Acad Sci U SA,1989.86(22):p.8946-50.
23. Dower, S.K., et al., Detection and characterization of high affinity plasma membrane receptors for human interleukin 1. J Exp Med,1985.162(2):p.501-15.
24. Auron, P.E., The interleukin 1 receptor:ligand interactions and signal transduction. Cytokine Growth Factor Rev,1998.9(3-4):p.221-37.
25. Sims, J.E. and S.K. Dower, Interleukin-1 receptors. Eur Cytokine Netw,1994.5(6):p.539-46.
26. Einstein, R., et al., Type 1 IL-1 receptor:ligand specific confirmation differences and the role of glycosylation in ligand binding. Cytokine,1996.8(3):p.206-13.
27. Vigers, G.R, et al., Crystal structure of the type-I interleukin-1 receptor complexed with interleukin-1 beta. Nature,1997.386(6621):p.190-4.
28. Martin, M. and K. Resch, Interleukin 1:more than a mediator between leukocytes. Trends Pharmacol Sci,1988.9(5):p.171-7.
29. Osborn, L, S. Kunkel, and GJ. Nabel, Tumor necrosis factor alpha and interleukin 1 stimulate the human immunodeficiency virus enhancer by activation of the nuclear factor kappa B. Proc Natl Acad Sci U S A,1989.86(7):p.2336-40.
30. Pruitt, J.H., et al., Increased soluble interleukin-1 type II receptor concentrations in postoperative patients and in patients with sepsis syndrome. Blood,1996.87(8):p.3282-8.
31. Arend, W.P., et al., Binding of IL-1 alpha, IL-1 beta, and IL-1 receptor antagonist by soluble IL-1 receptors and levels of soluble IL-1 receptors in synovial fluids. J Immunol,1994. 153(10):p.4766-74.
32. Fernandez-Botran, R., P.M. Chilton, and Y. Ma, Soluble cytokine receptors:their roles in immunoregulation, disease, and therapy. Adv Immunol,1996.63:p.269-336.
33. Ghivizzani, S.C., et al., Direct adenovirus-mediated gene transfer of interleukin 1 and tumor necrosis factor alpha soluble receptors to rabbit knees with experimental arthritis has local and distal anti-arthritic effects. Proc Natl Acad Sci U S A,1998.95(8):p.4613-8.
34. Sporri, B., et al., Soluble IL-1 receptor type I binds to human dermal fibroblasts and induces calcium flux. FEBS Lett,1998.434(3):p.283-8.
35. Subramaniam, S., et al., Cloning of a Salmo salar interleukin-1 receptor-like cDNA. Dev Comp Immunol,2002.26(5):p.415-31.
36. McMahan, C.J., et al., A novel IL-1 receptor, cloned from B cells by mammalian expression, is expressed in many cell types. EMBO J,1991.10(10):p.2821-32.
37. Colotta, F., et al., Interleukin-1 type Ⅱ receptor:a decoy target for IL-1 that is regulated by IL-4. Science,1993.261(5120):p.472-5.
38. Colotta, F., et al., The type Ⅱ'decoy'receptor:a novel regulatory pathway for interleukin 1. Immunol Today,1994.15(12):p.562-6.
39. Symons, J.A., PR. Young, and GW. Duff, Soluble type II interleukin 1 (IL-1) receptor binds and blocks processing of IL-1 beta precursor and loses affinity for IL-1 receptor antagonist. Proc Natl Acad Sci U S A,1995.92(5):p.1714-8.
40. Kollewe, C., D. Neumann, and M.U. Martin, The first two N-terminal immunoglobulin-like domains of soluble human IL-1 receptor type II are sufficient to bind and neutralize IL-lbeta. FEBS Lett,2000.487(2):p.189-93.
41. Sims, J.E., S.L. Painter, and I.R. Gow, Genomic organization of the type Ⅰ and type Ⅱ IL-1 receptors. Cytokine,1995.7(6):p.483-90.
42. Greenfeder, S.A., et al., Molecular cloning and characterization of a second subunit of the interleukin 1 receptor complex. J Biol Chem,1995.270(23):p.13757-65.
43. Dale, M., et al, The human gene encoding the interleukin-1 receptor accessory protein (ILIRAP) maps to chromosome 3q28 by fluorescence in situ hybridization and radiation hybrid mapping. Genomics,1998.47(2):p.325-6.
44. Wesche, H., K. Resch, and M.U. Martin, Effects of IL-1 receptor accessory protein on IL-1 binding. FEBS Lett,1998.429(3):p.303-6.
45. Cullinan, E.B., et al., IL-1 receptor accessory protein is an essential component of the IL-1 receptor. J Immunol,1998.161(10):p.5614-20.
46. Wesche, H., et al., The interleukin-1 receptor accessory protein (IL-lRAcP) is essential for IL-1-induced activation of interleukin-1 receptor-associated kinase (IRAK) and stress-activated protein kinases (SAP kinases). J Biol Chem,1997.272(12):p.7727-31.
47. Casadio, R., et al., Model of interaction of the IL-1 receptor accessory protein IL-lRAcP with the IL-1 beta/IL-lR(1) complex. FEBS Lett,2001.499(1-2):p.65-8.
48. Jensen, L.E., et al., IL-1 signaling cascade in liver cells and the involvement of a soluble form of the IL-1 receptor accessory protein. J Immunol,2000.164(10):p.5277-86.
49. Lovenberg, T.W., et al., Cloning of a cDNA encoding a novel interleukin-1 receptor related protein (IL lR-rp2). J Neuroimmunol,1996.70(2):p.113-22.
50. Debets, R., et al., Two novel IL-1 family members, IL-1 delta and IL-1 epsilon, function as an antagonist and agonist of NF-kappa B activation through the orphan IL-1 receptor-related protein 2. J Immunol,2001.167(3):p.1440-6.
51. Born, T.L., et al., Identification and characterization of two members of a novel class of the interleukin-1 receptor (IL-1 R) family. Delineation of a new class of IL-1 R-related proteins based on signaling. J Biol Chem,2000.275(39):p.29946-54.
52. Carrie, A., et al., A new member of the IL-1 receptor family highly expressed in hippocampus and involved in X-linked mental retardation. Nat Genet,1999.23(1):p.25-31.
53. Jin, H., et al., Two novel members of the interleukin-1 receptor gene family, one deleted in Xp22.1-Xp21.3 mental retardation. Eur J Hum Genet,2000.8(2):p.87-94.
54. Gay, N.J. and F.J. Keith, Drosophila Toll and IL-1 receptor. Nature,1991.351(6325):p. 355-6.
55. Liu, C., et al., Rat homolog of mouse interleukin-1 receptor accessory protein:cloning, localization and modulation studies. J Neuroimmunol,1996.66(1-2):p.41-8.
56. Smith, D.E., et al., Four new members expand the interleukin-1 superfamily. J Biol Chem, 2000.275(2):p.1169-75.
57. Sana, T.R., et al., Computational identification, cloning, and characterization of lL-lR9, a novel interleukin-1 receptor-like gene encoded over an unusually large interval of human chromosome Xq22.2-q22.3. Genomics,2000.69(2):p.252-62.
58. Norris, J.L. and J.L. Manley, Regulation of dorsal in cultured cells by Toll and tube:tube function involves a novel mechanism. Genes Dev,1995.9(3):p.358-69.
59. Akira, S., The role of IL-18 in innate immunity. Curr Opin Immunol,2000.12(1):p.59-63.
60. Bazan, J.F., J.C. Timans, and R.A. Kastelein, A newly defined interleukin-1? Nature,1996. 379(6566):p.591.
61. Torigoe, K., et al., Purification and characterization of the human interleukin-18 receptor. J Biol Chem,1997.272(41):p.25737-42.
62. Parnet, P., et al., IL-lRrp is a novel receptor-like molecule similar to the type 1 interleukin-1 receptor and its homologues T1/ST2 andIL-lR AcP. J Biol Chem,1996.271(8):p.3967-70.
63. Okamura, H., et al., Cloning of a new cytokine that induces IFN-gamma production by T cells. Nature,1995.378(6552):p.88-91.
64. Born, T.L., et al., Cloning of a novel receptor subunit, AcPL, required for interleukin-18 signaling. J Biol Chem,1998.273(45):p.29445-50.
65. Novick, D., et al., Interleukin-18 binding protein:a novel modulator of the Thl cytokine response. Immunity,1999.10(1):p.127-36.
66. Kumar, S., et al., Identification and initial characterization of four novel members of the interleukin-1 family. J Biol Chem,2000.275(14):p.10308-14.
67. Pan, G., et al.,1L-1H, an interleukin 1-related protein that binds IL-18 receptor/IL-lRrp. Cytokine,2001.13(1):p.1-7.
68. Klemenz, R., et al., The v-mos and c-Ha-ras oncoproteins exert similar effects on the pattern of protein synthesis. Oncogene,1989.4(6):p.799-803.
69. Tominaga, S., et al., Molecular cloning of the murine ST2 gene. Characterization and chromosomal mapping. Biochim BiophysActa,1991.1090(1):p.1-8.
70. Lanahan, A., et al., Growth factor-induced delayed early response genes. Mol Cell Biol,1992. 12(9):p.3919-29.
71. Bergers, G., et al., Alternative promoter usage of the Fos-responsive gene Fit-1 generates mRNA isoforms coding for either secreted or membrane-bound proteins related to the IL-1 receptor. EMBO J,1994.13(5):p.1176-88.
72. Li, H., et al., The cloning and nucleotide sequence of human ST2L cDNA. Genomics,2000. 67(3):p.284-90.
73. Tominaga, S., et al., Presence and expression of a novel variant form of ST2 gene product in human leukemic cell line UT-7/GM. Biochem Biophys Res Commun,1999.264(1):p.14-8.
74. Iwahana, H., et al., Different promoter usage and multiple transcription initiation sites of the interleukin-1 receptor-related human ST2 gene in VT-7 and TM12 cells. Eur J Biochem,1999. 264(2):p.397-406.
75. Gachter, T., A.K. Werenskiold, and R. Klemenz, Transcription of the interleukin-1 receptor-related T1 gene is initiated at different promoters in mast cells and fibroblasts. J Biol Chem,1996.271(1):p.124-9.
76. Schmitz, J., et al., 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, 2005.23(5):p.479-490.
77. Lohning, M., et al., T1/ST2 is preferentially expressed on murine Th2 cells, independent of interleukin 4, interleukin 5, and interleukin 10, and important for Th2 effector function. Proc Natl Acad Sci U S A,1998.95(12):p.6930-5.
78. Brint, E.K., et al., ST2 is an inhibitor of interleukin 1 receptor and Toll-like receptor 4 signaling and maintains endotoxin tolerance. Nat Immunol,2004.5(4):p.373-9.
79. Stansberg, C., et al., Cloning and characterisation of a putative ST2L homologue from Atlantic salmon (Salmo salar). Fish Shellfish Immunol,2003.15(3):p.211-24.
80. Fitzgerald, K.A. and L.A. O'Neill, The role of the interleukin-1/Toll-like receptor superfamily in inflammation and host defence. Microbes Infect,2000.2(8):p.933-43.
81. Frantz, S., R.A. Kelly, and T. Bourcier, Role of TLR-2 in the activation of nuclear factor kappaB by oxidative stress in cardiac myocytes. J Biol Chem,2001.276(7):p.5197-203.
82. Hayashi, F., et al., The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature,2001.410(6832):p.1099-103.
83. Hemmi, H., et al., A Toll-like receptor recognizes bacterial DNA. Nature,2000.408(6813):p. 740-5.
84. Muzio, M., et al., The human toll signaling pathway:divergence of nuclear factor kappaB and JNK/SAPK activation upstream of tumor necrosis factor receptor-associated factor 6 (TRAF6). J Exp Med,1998.187(12):p.2097-101.
85. Burns, K., et al., Tollip, a new component of the IL-lRI pathway, links IRAK to the IL-1 receptor. Nat Cell Biol,2000.2(6):p.346-51.
86. Medzhitov, R., et al., MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. Mol Cell,1998.2(2):p.253-8.
87. Muzio, M., et al., IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling. Science,1997.278(5343):p.1612-5.
88. Cao, Z., W.J. Henzel, and X. Gao, IRAK:a kinase associated with the interleukin-1 receptor. Science,1996.271(5252):p.1128-31.
89. Wesche, H., et al., IRAK-M is a novel member of the Pelle/interleukin-1 receptor-associated kinase (IRAK) family. J Biol Chem,1999.274(27):p.19403-10.
90. Bulut, Y., et al., Cooperation of Toll-like receptor 2 and 6 for cellular activation by soluble tuberculosis factor and Borrelia burgdorferi outer surface protein A lipoprotein:role of Toll-interacting protein and IL-1 receptor signaling molecules in Toll-like receptor 2 signaling. J Immunol,2001.167(2):p.987-94.
91. Ninomiya-Tsuji, J., et al., The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase cascade in the IL-1 signalling pathway. Nature,1999.398(6724):p.252-6.
92. Kopp, E., et al., ECSIT is an evolutionarily conserved intermediate in the Toll/IL-1 signal transductionpathway. Genes Dev,1999.13(16):p.2059-71.
93. Leonardi, A., et al., Physical and functional interaction of filamin (actin-binding protein-280) and tumor necrosis factor receptor-associated factor 2. J Biol Chem,2000.275(1):p.271-8.
94. Jefferies, C.A. and L.A. O'Neill, Racl regulates interleukin 1-induced nuclear factor kappaB activation in an inhibitory protein kappaBalpha-independent manner by enhancing the ability of the p65 subunit to transactivate gene expression. J Biol Chem,2000.275(5):p.3114-20.
95. Gewirtz, A.T., et al., Cutting edge:bacterial flagellin activates basolaterally expressed TLR5 to induce epithelial proinflammatory gene expression. J Immunol,2001.167(4):p.1882-5.
96. Janssens, S. and R. Beyaert, A universal role for MyD88 in TLR/IL-lR-mediated signaling. Trends Biochem Sci,2002.27(9):p.474-82.
97. Lomaga, M.A., et al., TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Genes Dev,1999.13(8):p.1015-24.
98. Jensen, L.E. and A.S. Whitehead, IRAKlb, a novel alternative splice variant of interleukin-1 receptor-associated kinase (IRAK), mediates interleukin-1 signaling and has prolonged stability. J Biol Chem,2001.276(31):p.29037-44.
99. Li, S., et al., IRAK-4:a novel member of the IRAK family with the properties of an IRAK-kinase. Proc Natl Acad Sci U S A,2002.99(8):p.5567-72.
100. Yamin, T.T. and D.K. Miller, The interleukin-1 receptor-associated kinase is degraded by proteasomes following its phosphorylation. J Biol Chem,1997.272(34):p.21540-7.
101. Phelan, P.E., M.T. Mellon, and C.H. Kim, Functional characterization of full-length TLR3, IRAK-4, and TRAF6 in zebrafish (Danio rerio). Mol Immunol,2005.42(9):p.1057-71.
102. Liu, Y., et al, A unique feature of Toll/IL-1 receptor domain-containing adaptor protein is partially responsible for lipopolysaccharide insensitivity in zebrafish with a highly conserved function of MyD88. J Immunol.185(6):p.3391-400.
103. Hulbert, S.H., et al., Resistance gene complexes:evolution and utilization Annu Rev Phytopathol,2001.39:p.285-312.
104. Anderson, K.V., L. Bokla, and C. Nusslein-Volhard, Establishment of dorsal-ventral polarity in the Drosophila embryo:the induction of polarity by the Toll gene product. Cell,1985.42(3): p.791-8.
105. Anderson, K.V., G. Jurgens, and C. Nusslein-Volhard, Establishment of dorsal-ventral polarity in the Drosophila embryo:genetic studies on the role of the Toll gene product. Cell,1985. 42(3):p.779-89.
106. Lemaitre, B., et al., The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell,1996.86(6):p.973-83.
107. Johnson, G.B., et al., Evolutionary clues to the functions of the Toll-like family as surveillance receptors. Trends Immunol,2003.24(1):p.19-24.
108. Kimbrell, D.A. and B. Beutler, The evolution and genetics of innate immunity. Nat Rev Genet, 2001.2(4):p.256-67.
109. Luo, C. and L. Zheng, Independent evolution of Toll and related genes in insects and mammals. Immunogenetics,2000.51(2):p.92-8.
110. Sangrador-Vegas, A., et al., Cloning and characterization of the rainbow trout (Oncorhynchus mykiss) type Ⅱ interleukin-1 receptor cDNA. Eur J Biochem,2000.267(24):p.7031-7.
111. Ottaviani, E., et al., Cytokines and invertebrate immune responses. Biol Cell,1995.85(1):p. 87-91.
112. Beck, G, T.W. Ellis, and N. Truong, Characterization of an IL-1 receptor from Asterias forbesi coelomocytes. Cell Immunol,2000.203(1):p.66-73.
113. Pujol, N., et al., A reverse genetic analysis of components of the Toll signaling pathway in Caenorhabditis elegans. Curr Biol,2001.11(11):p.809-21.
114. Zhang, G. and S. Ghosh, Negative regulation of toll-like receptor-mediated signaling by Tollip. J Biol Chem,2002.277(9):p.7059-65.
115. Garlanda, C., H.J. Anders, and A. Mantovani, TIR8/SIGIRR:an IL-1R/TLR family member with regulatory functions in inflammation and T cell polarization. Trends in Immunology, 2009.30(9):p.439-446.
116. Thomassen, E., B.R. Renshaw, and J.E. Sims, Identification and characterization ofSIGIRR, a molecule representing a novel subtype of the IL-1R superfamily. Cytokine,1999.11(6):p. 389-99.
117. Riva, F., et al., The expression pattern of TIR8 is conserved among vertebrates. Veterinary Immunology and Immunopathology,2009.131(1-2):p.44-49.
118. Lech, M., et al., Different roles of TiR8/Sigirr on toll-like receptor signaling in intrarenal antigen-presenting cells and tubular epithelial cells. Kidney Int,2007.72(2):p.182-92.
119. Polentarutti, N., et al., Unique pattern of expression and inhibition of IL-1 signaling by the IL-1 receptor family member TIR8/SIGIRR. Eur Cytokine Netw,2003.14(4):p.211-8.
120. Xiao, H., et al., The Toll-interleukin-1 receptor member SIGIRR regulates colonic epithelial homeostasis, inflammation, and tumorigenesis. Immunity,2007.26(4):p.461-75.
121. Garlanda, C, et al., Intestinal inflammation in mice deficient in Tir8, an inhibitory member of the IL-1 receptor family. Proc Natl Acad Sci U S A,2004.101(10):p.3522-6.
122. Huang, X., et al., SIGIRR promotes resistance against Pseudomonas aeruginosa keratitis by down-regulating type-1 immunity and IL-lR1 and TLR4 signaling. J Immunol,2006.177(1):p. 548-56.
123. Adib-Conquy, M., et al., Up-regulation of MyD88s and SIGIRR, molecules inhibiting Toll-like receptor signaling, in monocytes from septic patients. Crit Care Med,2006.34(9):p.2377-85.
124. Batliwalla, F.M., et al., Microarray analyses of peripheral blood cells identifies unique gene expression signature in psoriatic arthritis. Mol Med,2005.11(1-12):p.21-9.
125. Bulek, K., et al., The essential role of single Ig IL-1 receptor-related molecule/Toll IL-lR8 in regulation of Th.2 immune response. J Immunol,2009.182(5):p.2601-9.
126. Costelloe, C., et al., IL-lF5 mediates anti-inflammatory activity in the brain through induction of IL-4 following interaction with SIGIRR/TIR8. J Neurochem,2008.105(5):p.1960-9.
127. Wald, D., et al., SIGIRR, a negative regulator of Toll-like receptor-interleukin 1 receptor signaling. Nat Immunol,2003.4(9):p.920-7.
128. Qin, J.Z., et al., SIGIRR inhibits interleukin-1 receptor-and toll-like receptor 4-mediated signaling through different mechanisms. Journal of Biological Chemistry,2005.280(26):p. 25233-25241.
129. Lech, M., et al., Tir8/Sigirr prevents murine lupus by suppressing the immunostimulatory effects of lupus autoantigens. J Exp Med,2008.205(8):p.1879-88.
130. Rakoff-Nahoum, S., et al., Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell,2004.118(2):p.229-41.
131. Karin, M., T. Lawrence, and V. Nizet, Innate immunity gone awry:linking microbial infections to chronic inflammation and cancer. Cell,2006.124(4):p.823-35.
132. Mantovani, A., et al., Cancer-related inflammation. Nature,2008.454(7203):p.436-44.
133. Becker, C., et al., TGF-beta suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling. Immunity,2004.21(4):p.491-501.
134. Garlanda, C., et al., Damping excessive inflammation and tissue damage in Mycobacterium tuberculosis infection by Toll IL-1 receptor 8/single Ig IL-1-related receptor, a negative regulator of IL-1/TLR signaling. J Immunol,2007.179(5):p.3119-25.
135. Karin, M., Nuclear factor-kappaB in cancer development and progression. Nature,2006. 441(7092):p.431-6.
136. Curie], T.J., et al, Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med,2004.10(9):p.942-9.
137. Vetrano, S., et al., The lymphatic system controls intestinal inflammation and inflammation-associated Colon Cancer through the chemokine decoy receptor D6. Gut.59(2): p.197-206.
138. Mizukami, Y., et al., Induction of interleukin-8 preserves the angiogenic response in HIF-1 alpha-deficient colon cancer cells. Nat Med,2005.11(9):p.992-7.
139. Wang, D., et al., CXCL1 induced by prostaglandin E2 promotes angiogenesis in colorectal cancer. J Exp Med,2006.203(4):p.941-51.
140. Garlanda, C., et al., Increased susceptibility to colitis-associated cancer of mice lacking TIR8, an inhibitory member of the interleukin-1 receptor family. Cancer Res,2007.67(13):p. 6017-21.
141. Bozza, S., et al., Lack of Toll IL-1R8 exacerbates Th17 cell responses in fungal infection. J Immunol,2008.180(6):p.4022-31.
142. Bekker, L.G, et al., Immunopathologic effects of tumor necrosis factor alpha in murine mycobacterial infection are dose dependent. Infect Immun,2000.68(12):p.6954-61.
143. Harrington, L.E., et al., Interleukin 17-producing CD4+effector T cells develop via a lineage distinct from the T helper type I and 2 lineages. Nat Immunol,2005.6(11):p.1123-32.
144. Park, H., et al., A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol,2005.6(11):p.1133-41.
145. Zelante, T., et al., IL-23 and the Thl 7 pathway promote inflammation and impair antifungal immune resistance. Eur J Immunol,2007.37(10):p.2695-706.
146. Bellocchio, S., et al., The contribution of the Toll-like/IL-1 receptor superfamily to innate and adaptive immunity to fungal pathogens in vivo, J Immunol,2004.172(5):p.3059-69.
147. De Luca, A., et al., Functional yet balanced reactivity to Candida albicans requires TRIF, MyD88, and IDO-dependent inhibition of Rorc. J Immunol,2007.179(9):p.5999-6008.
148. Lau, C.M., et al., RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement. J Exp Med,2005.202(9):p.1171-7.
149. Leadbetter, E.A., et al., Chromatin-IgG complexes activate B cells by dual engagement of lgM and Toll-like receptors. Nature,2002.416(6881):p.603-7.
150. Marshak-Rothstein, A. and I.R. Rifkin, Immunologically active autoantigens:the role of toll-like receptors in the development of chronic inflammatory disease. Annu Rev Immunol, 2007.25:p.419-41.
151. Rahman, A. and D.A. Isenberg, Systemic lupus erythematosus. N Engl J Med,2008.358(9):p. 929-39.
152. Lech, M., et al., Resident dendritic cells prevent postischemic acute renal failure by help of single Ig IL-1 receptor-related protein. J Immunol,2009.183(6):p.4109-18.
153. Noris, M., et al., The Toll-IL-IR member Tir8/SIGIRR negatively regulates adaptive immunity against kidney grafts. J Immunol,2009.183(7):p.4249-60.
154. Zou, J., et al., Molecular cloning of interleukin lbeta from rainbow trout Oncorhynchus mykiss reveals no evidence of an ice cut site. Cytokine,1999.11(8):p.552-60.
155. Wang, T.H., et al., Identification of a Novel IL-1 Cytokine Family Member in Teleost Fish. Journal of Immunology,2009.183(2):p.962-974.
156. Goh, C.S., et al., Co-evolution of proteins with their interaction partners. Journal of Molecular Biology,2000.299(2):p.283-293.
157. Herbomel, P., B. Thisse, and C. Thisse, Ontogeny and behaviour of early macrophages in the zebrafish embryo. Development,1999.126(17):p.3735-45.
158. Stockhammer, O.W., et al., Transcriptome profiling and functional analyses of the zebrafish embryonic innate immune response to Salmonella infection. J Immunol,2009.182(9):p. 5641-53.
159. Willett, C.E., et al., Early hematopoiesis and developing lymphoid organs in the zebraflsh. Dev Dyn,1999.214(4):p.323-36.
160. Davidson, A.J. and L.I. Zon, The'definitive'(and'primitive') guide to zebrafish hematopoiesis. Oncogene,2004.23(43):p.7233-46.
161. Lam, S.H., et al., Development and maturation of the immune system in zebrafish, Danio rerio: a gene expression profiling, in situ hybridization and immunological study. Dev Comp Immunol,2004.28(1):p.9-28.
162. Burns, K., et al., Inhibition of interleukin 1 receptor/Toll-like receptor signaling through the alternatively spliced short form of MyD88 is due to its failure to recruit IRAK-4. J Exp Med, 2003.197(2):p.263-8.
163. Kobayashi, K., et al., IRAK-M is a negative regulator of Toll-like receptor signaling. Cell, 2002.110(2):p.191-202.
164. Kinjyo,1., et al., SOCS1/JAB is a negative regulator of LPS-induced macrophage activation. Immunity,2002.17(5):p.583-91.
165. Wu, X.Y., et al., Characterization, expression and evolution analysis of Toll-like receptor 1 gene in pujferfish (Tetraodon nigroviridis). Int J Immunogenet,2008.35(3):p.215-25.
166. Meijer, A.H., et al., Expression analysis of the Toll-like receptor and TIR domain adaptor families of zebrafish. Molecular Immunology,2004.40(11):p.773-783.
167. Roach, J.C., et al., The evolution of vertebrate Toll-like receptors. Proc Natl Acad Sci U S A, 2005.102(27):p.9577-82.
168. Huising, M.O., et al., The molecular evolution of the interleukin-1 family of cytokines; IL-18 in teleost fish. Developmental and Comparative Immunology,2004.28(5):p.395-413.
169. Matsuo, A., et al., Teleost TLR22 recognizes RNA duplex to induce IFN and protect cells from birnaviruses. J Immunol,2008.181(5):p.3474-85.
170. Ribeiro, C.M., et al., Evolution of recognition of ligands from Gram-positive bacteria: similarities and differences in the TLR2-mediated response between mammalian vertebrates and teleost fish. J Immunol.184(5):p.2355-68.
171. Sepulcre, M.R, et al., Evolution of lipopolysaccharide (LPS) recognition and signaling:fish TLR4 does not recognize LPS and negatively regulates NF-kappaB activation. J Immunol, 2009.182(4):p.1836-45.
172. Elbashir, S.M., et al., Analysis of gene function in somatic mammalian cells using small interfering RNAs. Methods,2002.26(2):p.199-213.
173. Kissler, S., et al., In vivo RNA interference demonstrates a role for Nrampl in modifying susceptibility to type 1 diabetes. Nat Genet,2006.38(4):p.479-83.
174. Ito, A., et al., Endotoxin-induced upregulation of type I interleukin-1 receptor mRNA expression in hepatocytes of mice:role of cytokines. J Interferon Cytokine Res,1997.17(1):p. 55-61.
175. Penton-Rol, G, et al., Bacterial lipopolysaccharide causes rapid shedding, followed by inhibition of mRNA expression, of the IL-1 type II receptor, with concomitant up-regulation of the type I receptor and induction of incompletely spliced transcripts. J Immunol,1999.162(5): p.2931-8.
176. Boraschi, D. and A. Tagliabue, The interleukin-1 receptor family. Vitam Horm,2006.74:p. 229-54.
177. Dinarello, C.A., Biologic basis for interleukin-1 in disease. Blood,1996.87(6):p.2095-147.
178. Schreuder, H., et al., A new cytokine-receptor binding mode revealed by the crystal structure of the IL-1 receptor with an antagonist. Nature,1997.386(6621):p.194-200.
179. Lopez-Castejon, G, et al., The type II interleukin-1 receptor (IL-IRII) of the bony fish gilthead seabream Sparus aurata is strongly induced after infection and tightly regulated at transcriptional andpost-transcriptional levels. Mol Immunol,2007.44(10):p.2772-80.