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Niedzielska, M.* ; Bodendorfer, B.* ; Münch, S.* ; Eichner, A.* ; Derigs, M.* ; da Costa, O.P.* ; Schweizer, A.* ; Neff, F. ; Nitschke, L.* ; Sparwasser, T.* ; Keyse, S.M.* ; Lang, R.*

Gene trap mice reveal an essential function of dual specificity phosphatase Dusp16/MKP-7 in perinatal survival and regulation of Toll-Like Receptor (TLR)-induced cytokine production.

J. Biol. Chem. 289, 2112-2126 (2014)
Verlagsversion Volltext DOI PMC
Open Access Gold
MAPK activity is negatively regulated by members of the dual specificity phosphatase (Dusp) family, which differ in expression, substrate specificity, and subcellular localization. Here, we investigated the function of Dusp16/MKP-7 in the innate immune system. The Dusp16 isoforms A1 and B1 were inducibly expressed in macrophages and dendritic cells following Toll-like receptor stimulation. A gene trap approach was used to generate Dusp16-deficient mice. Homozygous Dusp16tp/tp mice developed without gross abnormalities but died perinatally. Fetal liver cells from Dusp16tp/tp embryos efficiently reconstituted the lymphoid and myeloid compartments with Dusp16-deficient hematopoietic cells. However, GM-CSF-induced proliferation of bone marrow progenitors in vitro was impaired in the absence of Dusp16. In vivo challenge with Escherichia coli LPS triggered higher production of IL-12p40 in mice with a Dusp16-deficient immune system. In vitro, Dusp16-deficient macrophages, but not dendritic cells, selectively overexpressed a subset of TLR-induced genes, including the cytokine IL-12. Dusp16-deficient fibroblasts showed enhanced activation of p38 and JNK MAPKs. In macrophages, pharmacological inhibition and siRNA knockdown of JNK1/2 normalized IL-12p40 secretion. Production of IL-10 and its inhibitory effect on IL-12 production were unaltered in Dusp16tp/tp macrophages. Altogether, the Dusp16 gene trap mouse model identifies an essential role in perinatal survival and reveals selective control of differentiation and cytokine production of myeloid cells by the MAPK phosphatase Dusp16.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Cytokines/Interferon; Dendritic Cells; Dual Specificity Phosphatase; Endotoxin; Gene Knock-out; Gene Trap; Innate Immunity; MAP Kinases (MAPKs); Macrophages; Perinatal Lethality; Innate Immune-responses; Protein-kinase Phosphatase; Mouse Bone-marrow; Map Kinase; Interleukin-12 P40; Dendritic Cells; Inflammatory Responses; Activation; Macrophages; Differentiation
Sprache englisch
Veröffentlichungsjahr 2014
HGF-Berichtsjahr 2014
ISSN (print) / ISBN 0021-9258
e-ISSN 1083-351X
Zeitschrift Journal of Biological Chemistry, The
Quellenangaben Band: 289, Heft: 4, Seiten: 2112-2126 Artikelnummer: , Supplement: ,
Verlag American Society for Biochemistry and Molecular Biology
Verlagsort Bethesda
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Pathology (PATH)
POF Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Forschungsfeld(er) Enabling and Novel Technologies
PSP-Element(e) G-500300-001
PubMed ID 24311790
DOI 10.1074/jbc.M113.535245
WOS ID WOS:000331130200020
Scopus ID 84893035548
Erfassungsdatum 2014-02-13
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