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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)
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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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Publication type Article: Journal article
Document type Scientific Article
Keywords 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
Language english
Publication Year 2014
HGF-reported in Year 2014
ISSN (print) / ISBN 0021-9258
e-ISSN 1083-351X
Journal Journal of Biological Chemistry, The
Quellenangaben Volume: 289, Issue: 4, Pages: 2112-2126 Article Number: , Supplement: ,
Publisher American Society for Biochemistry and Molecular Biology
Publishing Place Bethesda
Reviewing status Peer reviewed
Institute(s) Institute of Pathology (PATH)
POF-Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Research field(s) Enabling and Novel Technologies
PSP Element(s) 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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