The wild-derived inbred mouse strain SPRET/Ei is resistant to LPS and defective in IFN-beta production.

2.50
Hdl Handle:
http://hdl.handle.net/10033/15956
Title:
The wild-derived inbred mouse strain SPRET/Ei is resistant to LPS and defective in IFN-beta production.
Authors:
Mahieu, Tina; Park, Jin Mo; Revets, Hilde; Pasche, Bastian; Lengeling, Andreas; Staelens, Jan; Wullaert, Andy; Vanlaere, Ineke; Hochepied, Tino; van Roy, Frans; Karin, Michael; Libert, Claude
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.
Affiliation:
Department for Molecular Biomedical Research, Flanders Interuniversity Institute for Biotechnology and Ghent University, Technologiepark 927, B-9052 Ghent, Belgium.
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.
Journal:
Proceedings of the National Academy of Sciences of the United States of America
Issue Date:
14-Feb-2006
URI:
http://hdl.handle.net/10033/15956
DOI:
10.1073/pnas.0510874103
PubMed ID:
16455798
Type:
Article
Language:
en
ISSN:
0027-8424
Appears in Collections:
publications of the department infection genetics (INFG)

Full metadata record

DC FieldValue Language
dc.contributor.authorMahieu, Tina-
dc.contributor.authorPark, Jin Mo-
dc.contributor.authorRevets, Hilde-
dc.contributor.authorPasche, Bastian-
dc.contributor.authorLengeling, Andreas-
dc.contributor.authorStaelens, Jan-
dc.contributor.authorWullaert, Andy-
dc.contributor.authorVanlaere, Ineke-
dc.contributor.authorHochepied, Tino-
dc.contributor.authorvan Roy, Frans-
dc.contributor.authorKarin, Michael-
dc.contributor.authorLibert, Claude-
dc.date.accessioned2008-01-11T10:24:09Z-
dc.date.available2008-01-11T10:24:09Z-
dc.date.issued2006-02-14-
dc.identifier.citationThe 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.en
dc.identifier.issn0027-8424-
dc.identifier.pmid16455798-
dc.identifier.doi10.1073/pnas.0510874103-
dc.identifier.urihttp://hdl.handle.net/10033/15956-
dc.description.abstractAlthough 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.en
dc.language.isoenen
dc.subject.meshAdaptor Proteins, Signal Transducingen
dc.subject.meshAnimalsen
dc.subject.meshBone Marrow Cellsen
dc.subject.meshDisease Susceptibilityen
dc.subject.meshDown-Regulationen
dc.subject.meshFeedback, Biochemicalen
dc.subject.meshFemaleen
dc.subject.meshInterferon-betaen
dc.subject.meshLeishmaniasis, Cutaneousen
dc.subject.meshLipopolysaccharidesen
dc.subject.meshListeria Infectionsen
dc.subject.meshListeria monocytogenesen
dc.subject.meshMacrophagesen
dc.subject.meshMaleen
dc.subject.meshMembrane Proteinsen
dc.subject.meshMiceen
dc.subject.meshMice, Inbred Strainsen
dc.subject.meshMyeloid Differentiation Factor 88en
dc.subject.meshReceptor, Interferon alpha-betaen
dc.subject.meshReceptors, Interferonen
dc.titleThe wild-derived inbred mouse strain SPRET/Ei is resistant to LPS and defective in IFN-beta production.en
dc.typeArticleen
dc.contributor.departmentDepartment for Molecular Biomedical Research, Flanders Interuniversity Institute for Biotechnology and Ghent University, Technologiepark 927, B-9052 Ghent, Belgium.en
dc.identifier.journalProceedings of the National Academy of Sciences of the United States of Americaen

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