Endotoxin-tolerant Mice Have Mutations in Toll-like Receptor 4 (Tlr4)
Autor: | Sophie Clermont, Danielle Malo, Gary Leveque, Line Larivière, Salman T. Qureshi, Karen J. Moore, Philippe Gros |
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Rok vydání: | 1999 |
Předmět: |
Lipopolysaccharides
DNA Mutational Analysis Molecular Sequence Data Immunology Mutant Mutation Missense Mice Inbred Strains Receptors Cell Surface Locus (genetics) Biology Mice Species Specificity Inbred strain Commentaries Animals Drosophila Proteins Humans Point Mutation Immunology and Allergy Amino Acid Sequence Cloning Molecular Allele Gene Expressed Sequence Tags Genetics Mice Inbred C3H Toll-like receptor Membrane Glycoproteins Sequence Homology Amino Acid Reverse Transcriptase Polymerase Chain Reaction Point mutation Homozygote Toll-Like Receptors Chromosome Mapping Molecular biology Endotoxemia Mice Mutant Strains Endotoxins Mice Inbred C57BL Toll-Like Receptor 4 Amino Acid Substitution TLR4 lipids (amino acids peptides and proteins) Sequence Alignment Gene Deletion Signal Transduction |
Zdroj: | The Journal of Experimental Medicine |
ISSN: | 1540-9538 0022-1007 |
Popis: | Bacterial lipopolysaccharide (LPS) provokes a vigorous, generalized proinflammatory state in the infected host. Genetic regulation of this response has been localized to the Lps locus on mouse chromosome 4, through study of the C3H/HeJ and C57BL/10ScCr inbred strains. Both C3H/HeJ and C57BL/10ScCr mice are homozygous for a mutant Lps allele (Lpsd/d) that confers hyporesponsiveness to LPS challenge, and therefore exhibit natural tolerance to its lethal effects. Genetic and physical mapping of 1,345 backcross progeny segregating this mutant phenotype confined Lps to a 0.9-cM interval spanning 1.7 Mb. Three transcription units were identified within the candidate interval, including Toll-like receptor 4 (Tlr4), part of a protein family with members that have been implicated in LPS-induced cell signaling. C3H/HeJ mice have a point mutation within the coding region of the Tlr4 gene, resulting in a nonconservative substitution of a highly conserved proline by histidine at codon 712, whereas C57BL/ 10ScCr mice exhibit a deletion of Tlr4. Identification of distinct mutations involving the same gene at the Lps locus in two different hyporesponsive inbred mouse strains strongly supports the hypothesis that altered Tlr4 function is responsible for endotoxin tolerance. |
Databáze: | OpenAIRE |
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