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

Niedzielska, Magdalena; Raffi, Faizal A M; Tel, Jurjen; Muench, Sandra; Jozefowski, Katrin; Alati, Nour; Lahl, Katharina LU ; Mages, Jörg; Billmeier, Ulrike and Schiemann, Matthias, et al. (2015) In Journal of Immunology 195(4). p.1753-1762
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.... (More)
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. (Less)
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Journal of Immunology
volume
195
issue
4
pages
1753 - 1762
publisher
American Association of Immunologists
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  • pmid:26170386
  • wos:000360013200045
  • scopus:84938946916
ISSN
1550-6606
DOI
10.4049/jimmunol.1400658
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English
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506ca0aa-bfe0-4288-aa8a-3989e9175fdb (old id 7749671)
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http://www.ncbi.nlm.nih.gov/pubmed/26170386?dopt=Abstract
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2015-08-08 01:26:30
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@article{506ca0aa-bfe0-4288-aa8a-3989e9175fdb,
  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.},
  author       = {Niedzielska, Magdalena and Raffi, Faizal A M and Tel, Jurjen and Muench, Sandra and Jozefowski, Katrin and Alati, Nour and Lahl, Katharina and Mages, Jörg and Billmeier, Ulrike and Schiemann, Matthias and Appelt, Uwe K and Wirtz, Stefan and Sparwasser, Tim and Hochrein, Hubertus and Figdor, Carl G and Keyse, Stephen M and Lang, Roland},
  issn         = {1550-6606},
  language     = {eng},
  number       = {4},
  pages        = {1753--1762},
  publisher    = {American Association of Immunologists},
  series       = {Journal of Immunology},
  title        = {Selective Expression of the MAPK Phosphatase Dusp9/MKP-4 in Mouse Plasmacytoid Dendritic Cells and Regulation of IFN-β Production.},
  url          = {http://dx.doi.org/10.4049/jimmunol.1400658},
  volume       = {195},
  year         = {2015},
}