• 1
    Vogel, S. N., Hansen, C. T. and Rosenstreich, D. L., Characterization of a congenitally LPS-resistant, athymic mouse strain. J. Immunol. 1979. 122: 619622.
  • 2
    Sultzer, B. M., Genetic control of host responses to endotoxin. Infect. Immun. 1972. 5: 107113.
  • 3
    Coutinho, A. and Meo, T., Genetic bases for unresponsiveness to lipopolysaccharide in C57BL/10Cr mice. Immunogenetics 1978. 7: 1724.
  • 4
    Vogel, S. N., The Lps gene. In Beutler, B. (Ed.) Tumor necrosis factors: The molecules and their emerging role in medicine. Raven Press, New York 1992, pp 485513.
  • 5
    Poltorak, A., He, X., Smirnova, I., Liu, M. Y., Huffel, C. V., Du, X., Birdwell, D., Alejos, E., Silva, M., Galanos, C., Freudenberg, M., Ricciardi-Castagnoli, P., Layton, B. and Beutler, B., Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 1998. 282: 20852088.
  • 6
    Imler, J. L. and Hoffmann, J. A., Toll receptors in innate immunity. Trends Cell Biol. 2001. 11: 304311.
  • 7
    Kimbrell, D. A. and Beutler, B., The evolution and genetics of innate immunity. Nat. Rev. Genet. 2001. 2: 256267.
  • 8
    Poltorak, A., Smirnova, I., Clisch, R. and Beutler, B., Limits of a deletion spanning Tlr4 in C57BL/10ScCr mice. J. Endotoxin Res. 2000. 6: 5156.
  • 9
    Bihl, F., Lariviere, L., Qureshi, S. T., Flaherty, L. and Malo, D., LPS-hyporesponsiveness of mnd mice is associated with a mutation in Toll-like receptor 4. Genes Immun. 2001. 2: 565.
  • 10
    Hoshino, K., Takeuchi, O., Kawai, T., Sanjo, H., Ogawa, T., Takeda, Y., Takeda, K. and Akira, S., Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J. Immunol. 1999. 162: 37493752.
  • 11
    Poltorak, A., Ricciardi-Castagnoli, P., Citterio, S. and Beutler, B., Physical contact between lipopolysaccharide and Toll-like receptor 4 revealed by genetic complementation. Proc. Natl. Acad. Sci. U S A 2000. 97: 21632167.
  • 12
    Lien, E., Means, T. K., Heine, H., Yoshimura, A., Kusumoto, S., Fukase, K., Fenton, M. J., Oikawa, M., Qureshi, N., Monks, B., Finberg, R. W., Ingalls, R. R. and Golenbock, D. T., Toll-like receptor 4 imparts ligand-specific recognition of bacterial lipopolysaccharide. J. Clin. Invest. 2000. 105: 497504.
  • 13
    Beutler, B., Du, X. and Poltorak, A., Identification of Toll-like receptor 4 (Tlr4) as the soleconduit for LPS signal transduction: genetic and evolutionary studies. J.  Endotoxin Res. 2001. 7: 277280.
  • 14
    Tapping, R. I., Akashi, S., Miyake, K., Godowski, P. J. and Tobias, P. S., Toll-like receptor 4, but not Toll-like receptor 2, is a signaling receptor for Escherichia and Salmonella lipopolysaccharides. J. Immunol. 2000. 165: 57805787.
  • 15
    Shimazu, R., Akashi, S., Ogata, H., Nagai, Y., Fukudome, K., Miyake, K. and Kimoto, M., MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4. J. Exp. Med. 1999. 189: 17771782.
  • 16
    Horng, T., Barton, G. M. and Medzhitov, R., TIRAP: an adapter molecule in the Toll signaling pathway. Nat. Immunol. 2001. 2: 835841.
  • 17
    Fitzgerald, K. A., Palsson-McDermott, E. M., Bowie, A. G., Jefferies, C. A., Mansell, A. S., Brady, G., Brint, E., Dunne, A., Gray, P., Harte, M. T., McMurray, D., Smith, D. E., Sims, J. E., Bird, T. A. and O'Neill, L. A., Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction. Nature 2001. 413: 7883.
  • 18
    Henneke, P. and Golenbock, D. T., TIRAP: how Toll receptors fraternize. Nat. Immunol. 2001. 2: 828830.
  • 19
    Nagai, Y., Akashi, S., Nagafuku, M., Ogata, M., Iwakura, Y., Akira, S., Kitamura, T., Kosugi, A., Kimoto, M. and Miyake, K., Essential role of MD-2 in LPS responsiveness and TLR4 distribution. Nat. Immunol. 2002. 3: 667672.
  • 20
    Kawai, T., Adachi, O., Ogawa, T., Takeda, K. and Akira, S., Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 1999. 11: 115122.
  • 21
    Horng, T., Barton, G. M., Flavell, R. A. and Medzhitov, R., The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors. Nature 2002. 420: 329333.
  • 22
    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., Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4. Nature 2002. 420: 324329.
  • 23
    Ahmad-Nejad, P., Hacker, H., Rutz, M., Bauer, S., Vabulas, R. M. and Wagner, H., Bacterial CpG-DNA and lipopolysaccharides activate Toll-like receptors at distinct cellular compartments. Eur. J. Immunol. 2002. 32: 19581968.
  • 24
    Zhang, G. and Ghosh, S., Toll-like receptor-mediated NF-kappa B activation: a phylogenetically conserved paradigm in innateimmunity. J. Clin. Invest. 2001. 107: 1319.
  • 25
    Kawai, T., Takeuchi, O., Fujita, T., Inoue, J., Muhlradt, P. F., Sato, S., Hoshino, K. and Akira, S., Lipopolysaccharide stimulates the MyD88-independentpathway and results in activation of IFN-regulatory factor 3 and the expression of a subset of lipopolysaccharide-inducible genes. J. Immunol. 2001. 167: 58875894.
  • 26
    Toshchakov, V., Jones, B. W., Perera, P. Y., Thomas, K., Cody, M. J., Zhang, S., Williams, B. R., Major, J., Hamilton, T. A., Fenton, M. J. and Vogel, S. N., TLR4, but not TLR2, mediates IFN-beta-induced STAT1 alpha/beta-dependent gene expression in macrophages. Nat. Immunol. 2002. 3: 392398.
  • 27
    Ogata, H., Su, I., Miyake, K., Nagai, Y., Akashi, S., Mecklenbrauker, I., Rajewsky, K., Kimoto, M. and Tarakhovsky, A., The Toll-like receptor protein RP105 regulates lipopolysaccharide signaling in B cells. J. Exp. Med. 2000. 192: 2329.
  • 28
    Thieblemont, N. and Wright, S. D., Transport of bacterial lipopolysaccharide to the golgi apparatus. J. Exp. Med. 1999. 190: 523534.
  • 29
    Hornef, M. W., Frisan, T., Vandewalle, A., Normark, S. and Richter-Dahlfors, A., Toll-like receptor 4 resides in the Golgi apparatus and colocalizes with internalized lipopolysaccharide in intestinal epithelial cells. J. Exp.Med. 2002. 195: 559570.
  • 30
    Akashi, S., Shimazu, R., Ogata, H., Nagai, Y., Takeda, K., Kimoto, M. and Miyake, K., Cutting edge: cell surface expression and lipopolysaccharide signaling via the Toll-like receptor 4-MD-2 complex on mouse peritoneal macrophages. J. Immunol. 2000. 164: 34713475.
  • 31
    Merlin, T., Woelky-Bruggmann, R., Fearns, C., Freudenberg, M. and Landmann, R., Expression and role of CD14 in mice sensitized to lipopolysaccharide by Propionibacterium acnes. Eur. J. Immunol. 2002. 32: 761772.
  • 32
    Matsuura, K., Ishida, T., Setoguchi, M., Higuchi, Y., Akizuki, S. and Yamamoto, S., Upregulation of mouse CD14 expression in Kupffer cells by lipopolysaccharide. J. Exp. Med. 1994. 179: 16711676.
  • 33
    Freudenberg, M. A. and Galanos, C., Metabolism of LPS in vivo. In Ryan, J. L. and Morrison, D. C. (Eds.) Bacterial endotoxic lipopolysaccharides, immunopharmacology and pathophysiology. CRC Press, Boca Raton 1992, pp 275294.
  • 34
    Galanos, C., Luderitz, O. and Westphal, O., Preparation and properties of a standardized lipopolysaccharide from Salmonella abortus equi (Novo-Pyrexal). Zentralbl. Bakteriol. [Orig. A] 1979. 243: 226244.
  • 35
    Hogan, B., Beddington, R., Constantini, F. and Lacy, E. (Eds.) Manipulating the mouse embryo: A laboratory manual. Cold Spring Harbor Laboratory Press, Cold Spring Harbor1994.
  • 36
    Freudenberg, M. A., Keppler, D. and Galanos, C., Requirement for lipopolysaccharide-responsive macrophages in galactosamine-induced sensitization to endotoxin. Infect. Immun. 1986. 51: 891895.
  • 37
    Chomczynski, P. and Sacchi, N., Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal. Biochem. 1987. 162: 156159.
  • 38
    Sing, A., Merlin, T., Knopf, H. P., Nielsen, P. J., Loppnow,H., Galanos, C. and Freudenberg, M. A., Bacterial induction of beta interferon in mice is a function of the lipopolysaccharide component. Infect. Immun. 2000. 68: 16001607.
  • 39
    Knopf, H. P., Otto, F., Engelhardt, R., Freudenberg, M. A., Galanos, C., Herrmann, F. and Schumann, R. R., Discordant adaptation of human peritoneal macrophages to stimulation by lipopolysaccharide and the synthetic lipid A analogue SDZ MRL 953. Down-regulation of TNF-alpha and IL-6 is paralleled by an up-regulation of IL-1 beta and granulocyte colony-stimulating factor expression. J. Immunol. 1994. 153: 287299.