Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text Full Text (PDF, 517K) PPT slides of all figures Correction (v189,p1519) Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JEM Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Qureshi, S. T. Articles by Malo, D. Search for Related Content PubMed PubMed Citation Articles by Qureshi, S. T. Articles by Malo, D. Social Bookmarking                            What's this?

Articles

Salman T. Qureshi^*,||, Line Larivière^||, Gary Leveque^||, Sophie Clermont^||, Karen J. Moore^¶, Philippe Gros^,||, and Danielle Malo^*,,||

From the ^* Department of Medicine, Department of Biochemistry, and Department of Human Genetics, McGill University, Montreal, Quebec, Canada H3G 1A4; the ^|| Centre for the Study of Host Resistance, Montreal General Hospital, Montreal, Quebec, Canada H3G 1A4; and ^¶ Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139

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 (Lps^d/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.

Key Words: lipopolysaccharide • inflammation • positional cloning • Salmonella • mice/ inbred C3H

Abbreviations used: EST, expressed sequence tag; LRR, leucine-rich repeat; NF, nuclear factor; ORF, open reading frame; PAPPA, pregnancy-associated plasma protein A; PFGE, pulsed field gel electrophoresis; RACE, rapid amplification of cDNA ends; RT, reverse transcription; SSCP, single-strand conformational polymorphism; SSLP, simple sequence length repeat; STS, sequence-tagged site; TIR, Toll IL-1 receptor; TLR, Toll-like receptor; Tlr4, murine Toll-like receptor 4; UTR, untranslated region.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

• Cureton, E. L., Ereso, A. Q., Victorino, G. P., Curran, B., Poole, D. P., Liao, M., Harken, A. H., Bhargava, A. (2009). Local Secretion of Urocortin 1 Promotes Microvascular Permeability during Lipopolysaccharide-Induced Inflammation. Endocrinology 150: 5428-5437 [Abstract] [Full Text]  
• Li, Y., Xiang, M., Yuan, Y., Xiao, G., Zhang, J., Jiang, Y., Vodovotz, Y., Billiar, T. R., Wilson, M. A., Fan, J. (2009). Hemorrhagic shock augments lung endothelial cell activation: role of temporal alterations of TLR4 and TLR2. Am. J. Physiol. Regul. Integr. Comp. Physiol. 297: R1670-R1680 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS