Endotoxin-tolerant mice have mutations in toll-like receptor 4 (Tlr4)

Bacterial lipopolysaccharide (LPS) provokes a vigorous, generalized proinfl ammatory state in the infected host. Genetic regulation of this response ha s been localized to the Lps locus on mouse chromosome 4, through study of t he C3H/HeJ and C57BL/10ScCr inbred strains. Both C3H/HeJ and C57BL/10ScCr m ice are homozygous for a mutant Lps allele (Lps(d/d)) that confers hyporesp onsiveness to LPS challenge, and therefore exhibit natural tolerance to its lethal effects. Genetic and physical mapping of 1,345 backcross progeny se gregating this mutant phenotype confined Lps to a 0.9-cM interval spanning 1.7 Mb. Three transcription units were identified within the candidate inte rval, including Toll-like receptor 4 (Tlr4), part of a protein family with members that have been implicated in LPS-induced cell signaling. C3H/HeJ mi ce have a point mutation within the coding region of the Tlr4 gene, resulti ng in a nonconservative substitution of a highly conserved proline by histi dine at codon 712, whereas C57BL/ 10ScCr mice exhibit a deletion of Tlr4, I dentification of distinct mutations involving the same gene at the Lps locu s in two different hyporesponsive inbred mouse strains strongly supports th e hypothesis that altered Tlr4 function is responsible for endotoxin tolera nce.