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

  title={Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene.},
  author={Alexander Poltorak and X P He and Irina I. Smirnova and M. Y. Liu and C van Huffel and X. Du and D Birdwell and E. Alejos and M Silva and Chris Galanos and Marina A. Freudenberg and Paola Ricciardi-Castagnoli and Bill Layton and Bruce Beutler},
  volume={282 5396},
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 Lpsd 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… 

Monoallelic expression of the murine gene encoding Toll-like receptor 4

Tlr4 is an autosomal gene whose expression is regulated similarly to that of genes on the X chromosome, and all cells from F1 mice from crosses of responder and C57BL/10ScCr mice express TLR4 protein.

Lps(d)/Ran of endotoxin-resistant C3H/HeJ mice is defective in mediating lipopolysaccharide endotoxin responses.

  • P. WongA. Kang S. Chung
  • Biology, Medicine
    Proceedings of the National Academy of Sciences of the United States of America
  • 1999
Lps/Ran is an important target for LPS-mediated signal transduction, and the Lps(d)/Ran gene may be useful as a therapeutic sequence in gene therapy for endotoxemia and septic shock.

Limits of a deletion spanning Tlr4 in C57BL/10ScCr mice

The exact limits of a deletion encompassing Tlr4 in the C57BL/10ScCr genome are defined to have phenotypic consequences that exceed the well known blockade of LPS signal transduction.

Genes other than TLR4 are involved in the response to inhaled LPS.

The results of this study indicate that although certain TLR4 mutations can be linked to a change in the LPS response phenotype, additional genes are clearly involved in determining the physiological and biological responses to inhaled LPS in mammals.

CD14 is required for MyD88-independent LPS signaling

The recessive mutation 'Heedless' (hdl) was detected in third-generation N-ethyl-N-nitrosourea–mutated mice that showed defective responses to microbial inducers, and the data suggest that the TLR4–MD-2 complex distinguishes LPS chemotypes, but CD14 nullifies this distinction.

Inherited IL-12 Unresponsiveness Contributes to the High LPS Resistance of the Lpsd C57BL/10ScCr Mouse1

A second genetic defect unrelated to the Lps/tlr4 mutation that underlies the IL-12 unresponsiveness and contributes to theLPS resistance and impaired innate immune response in this strain of mice is found.

Cutting edge: functional characterization of the effect of the C3H/HeJ defect in mice that lack an Lpsn gene: in vivo evidence for a dominant negative mutation.

Data presented herein demonstrate that F1 progeny from crosses between mice that carry a approximately 9-cM deletion of chromosome 4 and C3H/HeJ mice exhibit a pattern of LPS sensitivity, measured by TNF activity, that is indistinguishable from that exhibited by Lpsn x Lpsd F 1 progeny and whose average response is "intermediate" to parental responses.

Toll‐like receptor 4 expression levels determine the degree of LPS‐susceptibility in mice

In macrophages, investigation of the LPS‐induced cytokine (IL‐6) response revealed a linear relationship between the response and the logarithm ofTLR4–MD‐2 levels, indicating that TLR4 is the only limiting factor for LPS responsiveness in Cr mice.

Gene Product Lps the Lipopolysaccharide: Evidence for TLR4 as to (TLR4)-Deficient Mice Are Hyporesponsive Cutting Edge: Toll-Like Receptor 4

It is demonstrated that TLR4 is the gene product that regu-lates LPS response, and C3H/HeJ mice lackingTLR4 have a single point mutation of the amino acid that is highly conserved among the IL-1/Toll receptor family.



Characterization of a congenitally LPS-resistant, athymic mouse strain.

The combination of endotoxin unresponsiveness and the athymic nature of this mouse strain may provide a powerful new tool for studying the cellular events mediating endotoxicity.

The response of recombinant inbred strains of mice to bacterial lipopolysaccharides.

The association of the expression of the Mup-1 alleles with LPS responsiveness in the BXH strains suggests that the defective LPS response gene in C3H/HeJ mice is located on chromosome 4.

The primary role of lymphoreticular cells in the mediation of host responses to bacterial endotoxim.

The results demonstrate that lymphocytes and/or macrophages play a primary role in mediating a number of diverse and seemingly unrelated host responses to endotoxin.

Toll-like receptor-2 mediates lipopolysaccharide-induced cellular signalling

It is shown that Toll-like receptor 2 (TLR2) is a signalling receptor that is activated by LPS in a response that depends on LPS-binding protein and is enhanced by CD14, and that TLR2 is a direct mediator of signalling by L PS.

Genetic analysis of generation of serum interferon by bacterial lipopolysaccharide.

It was shown that this type of IF is stable to treatment at pH 2 for periods of time as long as 48 hr, but is labile to heating at 56 degrees C for 30 min.

Action of endotoxin on lymphoid cells.

It is suggested that spleen cells play an essential role in mediating the lethal effects of LPS in vivo, which is significantly more susceptible to LPS-induced lethality than previously thought.

Lipopolysaccharide Signals Activation of Tumor Necrosis Factor Biosynthesis Through the Ras/Raf-1/MEK/MAPK Pathway

The ras/raf-1/MEK/MAPK pathway is chiefly responsible for transduction of the LPS signal to the level of the TNF gene and mRNA and lies upstream from (or actually represent) the physical branchpoints of the transcriptional and translation activation signals generated by LPS.