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J Immunol. 2015 Aug 15;195(4):1753-62. doi: 10.4049/jimmunol.1400658. Epub 2015 Jul 13.

Selective Expression of the MAPK Phosphatase Dusp9/MKP-4 in Mouse Plasmacytoid Dendritic Cells and Regulation of IFN-β Production.

Author information

1
Institute of Clinical Microbiology, Immunology and Hygiene, University Hospital Erlangen, 91054 Erlangen, Germany;
2
Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, 6525 GA Nijmegen, the Netherlands;
3
Cancer Research UK Stress Response Laboratory, Division of Cancer Research, Medical Research Institute, University of Dundee, Jacqui Wood Cancer Centre, Ninewells Hospital and Medical School, Dundee DD1 9SY, United Kingdom;
4
Institute of Medical Microbiology, Immunology and Hygiene, Technical University Munich, 81675 Munich, Germany; Section of Virology, National Veterinary Institute, Technical University of Denmark, 1870 Frederiksberg, Denmark; Immunology Section, Lund University, 221 00 Lund, Sweden;
5
Institute of Medical Microbiology, Immunology and Hygiene, Technical University Munich, 81675 Munich, Germany;
6
Medical Clinic 1, University Hospital Erlangen, 91054 Erlangen, Germany;
7
Cell Sorting Unit, Nikolaus-Fiebiger-Center for Molecular Medicine, 91054 Erlangen, Germany;
8
Institute of Medical Microbiology, Immunology and Hygiene, Technical University Munich, 81675 Munich, Germany; TWINCORE-Centre for Experimental and Clinical Infection Research, 30625 Hannover, Germany; and.
9
Department of Research, Bavarian Nordic GmbH, 82152 Martinsried, Germany.
10
Institute of Clinical Microbiology, Immunology and Hygiene, University Hospital Erlangen, 91054 Erlangen, Germany; Institute of Medical Microbiology, Immunology and Hygiene, Technical University Munich, 81675 Munich, Germany; roland.lang@uk-erlangen.de.

Abstract

Plasmacytoid dendritic cells (pDCs) efficiently produce large amounts of type I IFN in response to TLR7 and TLR9 ligands, whereas conventional DCs (cDCs) predominantly secrete high levels of the cytokines IL-10 and IL-12. The molecular basis underlying this distinct phenotype is not well understood. In this study, we identified the MAPK phosphatase Dusp9/MKP-4 by transcriptome analysis as selectively expressed in pDCs, but not cDCs. We confirmed the constitutive expression of Dusp9 at the protein level in pDCs generated in vitro by culture with Flt3 ligand and ex vivo in sorted splenic pDCs. Dusp9 expression was low in B220(-) bone marrow precursors and was upregulated during pDC differentiation, concomitant with established pDC markers. Higher expression of Dusp9 in pDCs correlated with impaired phosphorylation of the MAPK ERK1/2 upon TLR9 stimulation. Notably, Dusp9 was not expressed at detectable levels in human pDCs, although these displayed similarly impaired activation of ERK1/2 MAPK compared with cDCs. Enforced retroviral expression of Dusp9 in mouse GM-CSF-induced cDCs increased the expression of TLR9-induced IL-12p40 and IFN-β, but not of IL-10. Conditional deletion of Dusp9 in pDCs was effectively achieved in Dusp9(flox/flox); CD11c-Cre mice at the mRNA and protein levels. However, the lack of Dusp9 in pDC did not restore ERK1/2 activation after TLR9 stimulation and only weakly affected IFN-β and IL-12p40 production. Taken together, our results suggest that expression of Dusp9 is sufficient to impair ERK1/2 activation and enhance IFN-β expression. However, despite selective expression in pDCs, Dusp9 is not essential for high-level IFN-β production by these cells.

PMID:
26170386
DOI:
10.4049/jimmunol.1400658
[Indexed for MEDLINE]
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