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

American Association for the Advancement of Science (AAAS) - Tập 282 Số 5396 - Trang 2085-2088 - 1998
Alexander Poltorak1, Xiaolong He1, Irina Smirnova1, Mu-Ya Liu1, Christophe Van Huffel1, Xin Du1, Dale Birdwell1, Erica Alejos1, Maria João Silva1, Chris Galanos1, Marina A. Freudenberg1, Paola Ricciardi‐Castagnoli1, Betsy Layton1, Bruce Beutler1
1A. 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.

Tóm tắt

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.

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We acknowledge the assistance of J. Turner A. Powelka R. Jain R. Clisch and C. Brady all summer undergraduate research fellows who worked with us to identify the Lps d mutation. We are also grateful to the Beutler Family Charitable Trust for providing funds for the purchase of an ABI model 373 sequencer.

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American Association for the Advancement of Science (AAAS)

Tập 282 Số 5396

2085-2088

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