A quantitative trait loci analysis to map genes involved in lipopolysaccharide-induced inflammatory response: identification of macrophage scavenger receptor 1 as a candidate gene.
Septic shock, which is a major complication observed after trauma and other human diseases, is likely the product of a prolonged and poorly controlled systemic inflammatory response. Symptoms of sepsis can be partially reproduced by injection of bacterial LPS in mice. Differences in mortality between C57BL/6J(high) and A/J(low) mice after LPS injection have been previously observed and correlated with differences in the inflammatory response between these two inbred strains. In the present study, we have mapped four loci responsible for differences in levels of LPS-induced IL-10, named modifier of IL-10, between the two strains. A locus within mouse chromosome 8 was confirmed using chromosome 8 consomic mice. This locus was further reduced in size by haplotype analysis and evaluated by the presence of potential candidate genes. The macrophage scavenger receptor 1 (Msr1) within this locus emerged as a candidate gene based on differences at the expression and structural levels between C57BL/6J and A/J mice. In comparison with wild-type (C57BL/6J) mice, Msr1 knockout mice displayed reduced levels of LPS-induced IL-10, but not of TNF-alpha or IL-6, confirming a specific role for this gene in the regulation of IL-10. These results suggest that Msr1 is involved in the regulation of the anti-inflammatory process, thus offering a new perspective on the molecular mechanisms involved in endotoxemia and sepsis.
Fulton
William B
WB
Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Reeves
Roger H
RH
Takeya
Motohiro
M
De Maio
Antonio
A
D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects*; D007249:Inflammation / Q000097:blood / Q000139:chemically induced* / Q000235:genetics*; D016753:Interleukin-10 / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D040641:Quantitative Trait Loci / Q000235:genetics*; D051117:Scavenger Receptors, Class A / Q000235:genetics* / Q000378:metabolism*
D008070:Lipopolysaccharides; C495140:Msr1 protein, mouse; D051117:Scavenger Receptors, Class A; D016753:Interleukin-10