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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. 182, 572-580
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Reciprocal Expression and Signaling of TLR4 and TLR9 in the Pathogenesis and Treatment of Necrotizing Enterocolitis.
S. C. Gribar, C. P. Sodhi, W. M. Richardson, R. J. Anand, G. K. Gittes, M. F. Branca, A. Jakub, X.-h. Shi, S. Shah, J. A. Ozolek, et al. (2009)
J. Immunol. 182, 636-646
   Abstract »    Full Text »    PDF »
Toll-like receptor signaling: a critical modulator of cell survival and ischemic injury in the heart.
W. Chao (2009)
Am J Physiol Heart Circ Physiol 296, H1-H12
   Abstract »    Full Text »    PDF »
Recognition of Toxoplasma gondii by TLR11 Prevents Parasite-Induced Immunopathology.
F. Yarovinsky, S. Hieny, and A. Sher (2008)
J. Immunol. 181, 8478-8484
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A Critical Role for Type I IFN in Arthritis Development following Borrelia burgdorferi Infection of Mice.
J. C. Miller, Y. Ma, J. Bian, K. C. F. Sheehan, J. F. Zachary, J. H. Weis, R. D. Schreiber, and J. J. Weis (2008)
J. Immunol. 181, 8492-8503
   Abstract »    Full Text »    PDF »
Apolipoprotein A-II augments monocyte responses to LPS by suppressing the inhibitory activity of LPS-binding protein.
P. A. Thompson, J. F.P. Berbee, P. C.N. Rensen, and R. L. Kitchens (2008)
Innate Immunity 14, 365-374
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Continuous pharmacodynamic activity of eritoran tetrasodium, a TLR4 antagonist, during intermittent intravenous infusion into normal volunteers.
D. P. Rossignol, N. Wong, R. Noveck, and M. Lynn (2008)
Innate Immunity 14, 383-394
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TLR4-mediated activation of dendritic cells by the heat shock protein DnaK from Francisella tularensis.
A. R. Ashtekar, P. Zhang, J. Katz, C. C. S. Deivanayagam, P. Rallabhandi, S. N. Vogel, and S. M. Michalek (2008)
J. Leukoc. Biol. 84, 1434-1446
   Abstract »    Full Text »    PDF »
Mucosal Clearance of Capsule-Expressing Bacteria Requires Both TLR and Nucleotide-Binding Oligomerization Domain 1 Signaling.
T. A. Zola, E. S. Lysenko, and J. N. Weiser (2008)
J. Immunol. 181, 7909-7916
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TLR4 Facilitates Translocation of Bacteria across Renal Collecting Duct Cells.
C. Chassin, S. Vimont, F. Cluzeaud, M. Bens, J.-M. Goujon, B. Fernandez, A. Hertig, E. Rondeau, G. Arlet, M. W. Hornef, et al. (2008)
J. Am. Soc. Nephrol. 19, 2364-2374
   Abstract »    Full Text »    PDF »
Association analysis identifies TLR7 and TLR8 as novel risk genes in asthma and related disorders.
S Moller-Larsen, M Nyegaard, A Haagerup, J Vestbo, T A Kruse, and A D Borglum (2008)
Thorax 63, 1064-1069
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Mycobacterium avium Glycopeptidolipids Require Specific Acetylation and Methylation Patterns for Signaling through Toll-like Receptor 2.
L. Sweet, W. Zhang, H. Torres-Fewell, A. Serianni, W. Boggess, and J. Schorey (2008)
J. Biol. Chem. 283, 33221-33231
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Dendritic Cell Differentiation Induced by a Self-Peptide Derived from Apolipoprotein E.
T. A. Stephens, E. Nikoopour, B. J. Rider, M. Leon-Ponte, T. A. Chau, S. Mikolajczak, P. Chaturvedi, E. Lee-Chan, R. A. Flavell, S. M. M. Haeryfar, et al. (2008)
J. Immunol. 181, 6859-6871
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A New Mechanism for Inhalational Priming: IL-4 Bypasses Innate Immune Signals.
A. M. Dittrich, H.-C. Chen, L. Xu, P. Ranney, S. Connolly, T. O. Yarovinsky, and H. K. Bottomly (2008)
J. Immunol. 181, 7307-7315
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Evolution of MDA-5/RIG-I-dependent innate immunity: Independent evolution by domain grafting.
D. Sarkar, R. DeSalle, and P. B. Fisher (2008)
PNAS 105, 17040-17045
   Abstract »    Full Text »    PDF »
Studying host-pathogen interactions and innate immunity in Caenorhabditis elegans.
D. Kim (2008)
Dis. Model. Mech. 1, 205-208
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Salmonella virulence factor SpiC is involved in expression of flagellin protein and mediates activation of the signal transduction pathways in macrophages.
K.-i. Uchiya and T. Nikai (2008)
Microbiology 154, 3491-3502
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Accelerated Prion Disease Pathogenesis in Toll-Like Receptor 4 Signaling-Mutant Mice.
D. S. Spinner, I. S. Cho, S. Y. Park, J. I. Kim, H. C. Meeker, X. Ye, G. LaFauci, D. J. Kerr, M. J. Flory, B. S. Kim, et al. (2008)
J. Virol. 82, 10701-10708
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Signaling through MyD88 Regulates Leukocyte Recruitment after Brain Injury.
A. A. Babcock, H. Toft-Hansen, and T. Owens (2008)
J. Immunol. 181, 6481-6490
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Shiga Toxin-Mediated Disease in MyD88-Deficient Mice Infected with Escherichia coli O157:H7.
C. C. Toledo, T. J. Rogers, M. Svensson, R. Tati, H. Fischer, C. Svanborg, and D. Karpman (2008)
Am. J. Pathol. 173, 1428-1439
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Toll-like Receptor 4 Polymorphisms and Aspergillosis in Stem-Cell Transplantation.
P.-Y. Bochud, J. W. Chien, K. A. Marr, W. M. Leisenring, A. Upton, M. Janer, S. D. Rodrigues, S. Li, J. A. Hansen, L. P. Zhao, et al. (2008)
N. Engl. J. Med. 359, 1766-1777
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