The wild-derived inbred mouse strain SPRET/Ei is resistant to LPS and defective in IFN-beta production.
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Authors
Mahieu, TinaPark, Jin Mo
Revets, Hilde
Pasche, Bastian
Lengeling, Andreas
Staelens, Jan
Wullaert, Andy
Vanlaere, Ineke
Hochepied, Tino
van Roy, Frans
Karin, Michael
Libert, Claude
Issue Date
2006-02-14
Metadata
Show full item recordAbstract
Although activation of Toll-like receptor 4 (TLR4)-positive cells is essential for eliminating Gram-negative bacteria, overactivation of these cells by the TLR4 ligand LPS initiates a systemic inflammatory reaction and shock. Here we demonstrate that SPRET/Ei mice, derived from Mus spretus, exhibit a dominant resistance against LPS-induced lethality. This resistance is mediated by bone marrow-derived cells. Macrophages from these mice exhibit normal signaling and gene expression responses that depend on the myeloid differentiation factor 88 adaptor protein, but they are impaired in IFN-beta production. The defect appears to be specific for IFN-beta, although the SPRET/Ei IFN-beta promoter is normal. In vivo IFN-beta induction by LPS or influenza virus is very low in SPRET/Ei mice, but IFN-beta-treatment restores the sensitivity to LPS, and IFN type 1 receptor-deficient mice are also resistant to LPS. Because of the defective induction of IFN-beta, these mice are completely resistant to Listeria monocytogenes and highly sensitive to Leishmania major infection. Stimulation of SPRET/Ei macrophages leads to rapid down-regulation of IFN type 1 receptor mRNA expression, which is reflected in poor induction of IFN-beta-dependent genes. This finding indicates that the resistance of SPRET/Ei mice to LPS is due to disruption of a positive-feedback loop that amplifies IFN-beta production. In contrast to TLR4-deficient mice, SPRET/Ei mice resist both LPS and sepsis induced with Klebsiella pneumoniae.Citation
The wild-derived inbred mouse strain SPRET/Ei is resistant to LPS and defective in IFN-beta production. 2006, 103 (7):2292-7 Proc. Natl. Acad. Sci. U.S.A.Affiliation
Department for Molecular Biomedical Research, Flanders Interuniversity Institute for Biotechnology and Ghent University, Technologiepark 927, B-9052 Ghent, Belgium.PubMed ID
16455798Type
ArticleLanguage
enISSN
0027-8424ae974a485f413a2113503eed53cd6c53
10.1073/pnas.0510874103
Scopus Count