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PMID: 19923465 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

The Tpl2 mutation Sluggish impairs type I IFN production and increases susceptibility to group B streptococcal disease.

Journal of immunology (Baltimore, Md. : 1950) ·Vol. 183 ·No. 12 ·2009-12-15 ·Pages 7975-83

Xiao N, Eidenschenk C, Krebs P, Brandl K, Blasius AL, Xia Y, Khovananth K, Smart NG, Beutler B

Abstract

Sluggish was identified in a population of third generation mice descended from N-ethyl-N-nitrosourea-mutagenized sires. Macrophages from homozygotes exhibited impaired TNF-alpha production in response to all TLR ligands tested and displayed impaired type I IFN production in response to TLR7 and TLR9 stimulations. The phenotype was confined to a critical region on mouse chromosome 18 and then ascribed to a T to A transversion in the acceptor splice site of intron 4 at position 13346 of the Map3k8 gene, resulting in defective splicing. The Map3k8(Sluggish) mutation does not result in susceptibility to viral infections, but Sluggish mice displayed high susceptibility to group B streptococcus infection, with impaired TNF-alpha and type I IFN production in infected macrophages. Our data demonstrate that the encoded protein kinase Tpl2 plays an essential role in cell signaling in the immune response to certain pathogens.

MeSH Terms
Animals Ethylnitrosourea Genetic Predisposition to Disease Herpesviridae Infections/genetics,immunology Interferon Type I/antagonists & inhibitors,biosynthesis Listeriosis/genetics,immunology MAP Kinase Kinase Kinases/genetics,physiology Male Mice Mice, Inbred C3H Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Muromegalovirus/immunology Mutagenesis/immunology Proto-Oncogene Proteins/genetics,physiology RNA Splicing/genetics Signal Transduction/genetics,immunology Streptococcal Infections/enzymology,genetics,immunology Streptococcus agalactiae/immunology
Chemicals
Interferon Type I Proto-Oncogene Proteins MAP Kinase Kinase Kinases Map3k8 protein, mouse Ethylnitrosourea
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Xiao Nengming
Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037, USA.
Eidenschenk Celine
Krebs Philippe
Brandl Katharina
Blasius Amanda L
Xia Yu
Khovananth Kevin
Smart Nora G
Beutler Bruce
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Article Info
Journal
Journal of immunology (Baltimore, Md. : 1950)
Abbr.
J Immunol
ISSN
1550-6606
DOI
10.4049/jimmunol.0902718
Published
2009-12-15
Pages
7975-83
Language
English
Region
United States
NLM ID
2985117R
PMCID
PMC8424661
Subset
IM
Grants
NIAID NIH HHS · HHSN272200700038C · United States
NIAID NIH HHS · P01 AI070167 · United States
NIGMS NIH HHS · R01 GM060031 · United States
NIAID NIH HHS · 5P01AI070167 · United States
External Links
PubMed source DOI: 10.4049/jimmunol.0902718 PMC Full Text View journal details
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