Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: Mutations in Tlr4 gene

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

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Abstract

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 Lps(d) 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.

Original languageEnglish (US)
Pages (from-to)2085-2088
Number of pages4
JournalScience
Volume282
Issue number5396
DOIs
StatePublished - Dec 11 1998

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Cite this

Poltorak, A., He, X., Smirnova, I., Liu, M. Y., Van Huffel, C., Du, X., Birdwell, D., Alejos, E., Silva, M., Galanos, C., Freudenberg, M., Ricciardi-Castagnoli, P., Layton, B., & Beutler, B. (1998). Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: Mutations in Tlr4 gene. Science, 282(5396), 2085-2088. https://doi.org/10.1126/science.282.5396.2085