Gene trap mice reveal an essential function of Dusp16/MKP-7 in perinatal survival and regulation of TLR-induced cytokine production [Immunology]

December 5th, 2013 by Niedzielska, M., Bodendorfer, B., Munch, S., Eichner, A., Derigs, M., da Costa, O., Schweizer, A., Neff, F., Nitschke, L., Sparwasser, T., Keyse, S., Lang, R.

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 have investigated the function of Dusp16/MKP-7 in the innate immune system. The Dusp16 isoforms A1 and B1 were inducibly expressed in macrophages and DC following TLR 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 compartment 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 E. 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 over-expressed 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. Together, 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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