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

In English

Författare

  • Magdalena Niedzielska
  • Faizal A M Raffi
  • Jurjen Tel
  • Sandra Muench
  • Katrin Jozefowski
  • Nour Alati
  • Katharina Lahl
  • Jörg Mages
  • Ulrike Billmeier
  • Matthias Schiemann
  • Uwe K Appelt
  • Stefan Wirtz
  • Tim Sparwasser
  • Hubertus Hochrein
  • Carl G Figdor
  • Stephen M Keyse
  • Roland Lang
Visa allt

Summary, in English

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.

Publiceringsår

2015

Språk

Engelska

Sidor

1753-1762

Publikation/Tidskrift/Serie

Journal of Immunology

Volym

195

Issue

4

Dokumenttyp

Artikel i tidskrift

Förlag

American Association of Immunologists

Ämne

  • Immunology in the medical area

Status

Published

Forskningsgrupp

  • Mucosal Immunology

ISBN/ISSN/Övrigt

  • ISSN: 1550-6606