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The wild-derived inbred mouse strain SPRET/Ei is resistant to LPS and defective in IFN-beta production.
Mahieu, Tina Park, Jin Mo Revets, Hilde Pasche, Bastian Lengeling, Andreas Staelens, Jan Wullaert, Andy Vanlaere, Ineke Hochepied, Tino van Roy, Frans
Mahieu, Tina
Park, Jin Mo
Revets, Hilde
Pasche, Bastian
Lengeling, Andreas
Staelens, Jan
Wullaert, Andy
Vanlaere, Ineke
Hochepied, Tino
van Roy, Frans
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2006-02-14
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Abstract
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.
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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.
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en
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0027-8424