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Science 11 December 1998:
Vol. 282. no. 5396, pp. 2085 - 2088
DOI: 10.1126/science.282.5396.2085
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Reports

Defective LPS Signaling in C3H/HeJ and C57BL/10ScCr Mice: Mutations in Tlr4 Gene

Alexander Poltorak, Xiaolong He, * Irina Smirnova, Mu-Ya Liu, dagger Christophe Van Huffel, ddagger Xin Du, Dale Birdwell, Erica Alejos, Maria Silva, Chris Galanos, Marina Freudenberg, Paola Ricciardi-Castagnoli, Betsy Layton, Bruce Beutler §

Mutations of the gene Lps selectively impede lipopolysaccharide (LPS) signal transduction in C3H/HeJ and C57BL/10ScCr mice, rendering them resistant to endotoxin yet highly susceptible to Gram-negative infection. The codominant Lpsd allele of C3H/HeJ mice was shown to correspond to a missense mutation in the third exon of the Toll-like receptor-4 gene (Tlr4), predicted to replace proline with histidine at position 712 of the polypeptide chain. C57BL/10ScCr mice are homozygous for a null mutation of Tlr4. Thus, the mammalian Tlr4 protein has been adapted primarily to subserve the recognition of LPS and presumably transduces the LPS signal across the plasma membrane. Destructive mutations of Tlr4 predispose to the development of Gram-negative sepsis, leaving most aspects of immune function intact.

A. Poltorak, X. He, I. Smirnova, M.-Y. Liu, C. Van Huffel, X. Du, D. Birdwell, E. Alejos, M. Silva, B. Layton, B. Beutler, Howard Hughes Medical Institute and the Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75235-9050 USA. C. Galanos and M. Freudenberg, Max-Planck Institute für Immunobiologie, Freiburg, Germany. P. Ricciardi, CNR-Cellular and Molecular Pharmacology Center, Milan, Italy.
*   Present address: Northwestern University, 2300 Children's Plaza, No. 209, Chicago, IL 60614-3394, USA.

dagger    Present address: University of Texas Southwestern Medical Center, Department of Pharmacology, Dallas, TX 75235-9041 USA.

ddagger    Present address: Millennium, Inc., Cambridge, MA 02139-4815, USA.

§   To whom correspondence should be addressed at Howard Hughes Medical Institute, 5323 Harry Hines Boulevard, Dallas, TX 75235-9050, USA.

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J. Immunol. 181, 4354-4362
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TLR ligand-induced podosome disassembly in dendritic cells is ADAM17 dependent.
M. A. West, A. R. Prescott, K. M. Chan, Z. Zhou, S. Rose-John, J. Scheller, and C. Watts (2008)
J. Cell Biol. 182, 993-1005
   Abstract »    Full Text »    PDF »
Innate immune adaptor MyD88 mediates neutrophil recruitment and myocardial injury after ischemia-reperfusion in mice.
Y. Feng, H. Zhao, X. Xu, E. S. Buys, M. J. Raher, J. C. Bopassa, H. Thibault, M. Scherrer-Crosbie, U. Schmidt, and W. Chao (2008)
Am J Physiol Heart Circ Physiol 295, H1311-H1318
   Abstract »    Full Text »    PDF »
Clinical features and risk factors of postsurgical gout.
E H Kang, E Y Lee, Y J Lee, Y W Song, and E B Lee (2008)
Ann Rheum Dis 67, 1271-1275
   Abstract »    Full Text »    PDF »
Host species-specific usage of the TLR4-LPS receptor complex.
R. Lizundia, K.-S. Sauter, G. Taylor, and D. Werling (2008)
Innate Immunity 14, 223-231
   Abstract »    PDF »
A Triacylated Lipoprotein from Mycoplasma genitalium Activates NF-{kappa}B through Toll-Like Receptor 1 (TLR1) and TLR2.
T. Shimizu, Y. Kida, and K. Kuwano (2008)
Infect. Immun. 76, 3672-3678
   Abstract »    Full Text »    PDF »
The Absence of Toll-Like Receptor 4 Signaling in C3H/HeJ Mice Predisposes Them to Overwhelming Rickettsial Infection and Decreased Protective Th1 Responses.
J. M. Jordan, M. E. Woods, J. Olano, and D. H. Walker (2008)
Infect. Immun. 76, 3717-3724
   Abstract »    Full Text »    PDF »
Differential Activation of Human and Mouse Toll-Like Receptor 4 by the Adjuvant Candidate LpxL1 of Neisseria meningitidis.
L. Steeghs, A. M. Keestra, A. van Mourik, H. Uronen-Hansson, P. van der Ley, R. Callard, N. Klein, and J. P. M. van Putten (2008)
Infect. Immun. 76, 3801-3807
   Abstract »    Full Text »    PDF »
Oral sensitization with shrimp tropomyosin induces in mice allergen-specific IgE, T cell response and systemic anaphylactic reactions.
F. Capobianco, C. Butteroni, B. Barletta, S. Corinti, C. Afferni, R. Tinghino, M. Boirivant, and G. Di Felice (2008)
Int. Immunol. 20, 1077-1086
   Abstract »    Full Text »    PDF »
Therapeutic Administration of KM+ Lectin Protects Mice Against Paracoccidioides brasiliensis Infection via Interleukin-12 Production in a Toll-Like Receptor 2-Dependent Mechanism.
K. C. Coltri, L. L. Oliveira, C. F. Pinzan, P. E. Vendruscolo, R. Martinez, M. H. Goldman, A. Panunto-Castelo, and M.-C. Roque-Barreira (2008)
Am. J. Pathol. 173, 423-432
   Abstract »    Full Text »    PDF »
Osteal Tissue Macrophages Are Intercalated throughout Human and Mouse Bone Lining Tissues and Regulate Osteoblast Function In Vitro and In Vivo.
M. K. Chang, L.-J. Raggatt, K. A. Alexander, J. S. Kuliwaba, N. L. Fazzalari, K. Schroder, E. R. Maylin, V. M. Ripoll, D. A. Hume, and A. R. Pettit (2008)
J. Immunol. 181, 1232-1244
   Abstract »    Full Text »    PDF »
Modulation of Gene Expression via Disruption of NF-{kappa}B Signaling by a Bacterial Small Molecule.
V. V. Kravchenko, G. F. Kaufmann, J. C. Mathison, D. A. Scott, A. Z. Katz, D. C. Grauer, M. Lehmann, M. M. Meijler, K. D. Janda, and R. J. Ulevitch (2008)
Science 321, 259-263
   Abstract »    Full Text »    PDF »
Klebsiella oxytoca: opportunistic infections in laboratory rodents.
A. Bleich, P. Kirsch, H. Sahly, J. Fahey, A. Smoczek, H.-J. Hedrich, and J. P Sundberg (2008)
Lab Anim 42, 369-375
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Cellular trafficking of lipoteichoic acid and Toll-like receptor 2 in relation to signaling; role of CD14 and CD36.
N. J. Nilsen, S. Deininger, U. Nonstad, F. Skjeldal, H. Husebye, D. Rodionov, S. von Aulock, T. Hartung, E. Lien, O. Bakke, et al. (2008)
J. Leukoc. Biol. 84, 280-291
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Absence seizures in C3H/HeJ and knockout mice caused by mutation of the AMPA receptor subunit Gria4.
B. Beyer, C. Deleuze, V. A. Letts, C. L. Mahaffey, R. M. Boumil, T. A. Lew, J. R. Huguenard, and W. N. Frankel (2008)
Hum. Mol. Genet. 17, 1738-1749
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Pulmonary Surfactant Protein A Regulates TLR Expression and Activity in Human Macrophages.
L. N. Henning, A. K. Azad, K. V. L. Parsa, J. E. Crowther, S. Tridandapani, and L. S. Schlesinger (2008)
J. Immunol. 180, 7847-7858
   Abstract »    Full Text »    PDF »
Retinoic Acid-Inducible Gene-I Mediates Late Phase Induction of TNF-{alpha} by Lipopolysaccharide.
J. Wang, S. Wu, X. Jin, M. Li, S. Chen, J. L. Teeling, V. H. Perry, and J. Gu (2008)
J. Immunol. 180, 8011-8019
   Abstract »    Full Text »    PDF »


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