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

Niedzielska M, Bodendorfer B, Muench S, Eichner A, Derigs M, Da Costa O, Schweizer A, Neff F, Nitschke L, Sparwasser T, Keyse SM, Lang R (2014)

Publication Type: Journal article

Publication year: 2014

Journal

Publisher: American Society for Biochemistry and Molecular Biology

Book Volume: 289

Pages Range: 2112-26

Journal Issue: 4

DOI: 10.1074/jbc.M113.535245

Abstract

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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Involved external institutions

University of Dundee United Kingdom (GB) Technische Universität München (TUM) Germany (DE) Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich Germany (DE)

How to cite

APA:

Niedzielska, M., Bodendorfer, B., Muench, S., Eichner, A., Derigs, M., Da Costa, O.,... Lang, R. (2014). 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. Journal of Biological Chemistry, 289(4), 2112-26. https://doi.org/10.1074/jbc.M113.535245

MLA:

Niedzielska, Magdalena, et al. "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." Journal of Biological Chemistry 289.4 (2014): 2112-26.

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