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The MEK1/2-ERK Pathway Inhibits Type I IFN Production in Plasmacytoid Dendritic Cells
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SYSNO ASEP 0490084 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title The MEK1/2-ERK Pathway Inhibits Type I IFN Production in Plasmacytoid Dendritic Cells Author(s) Janovec, Vaclav (UMG-J)
Aouar, B. (FR)
Font-Haro, Albert (UMG-J)
Hofman, T. (CZ)
Trejbalová, Kateřina (UMG-J) RID
Weber, J. (CZ)
Chaperot, L. (FR)
Plumas, J. (FR)
Olive, D. (FR)
Dubreuil, P. (FR)
Nunes, J.A. (FR)
Stranska, R. (FR)
Hirsch, Ivan (UMG-J) ORCID, RIDNumber of authors 13 Article number 364 Source Title Frontiers in Immunology. - : Frontiers Media - ISSN 1664-3224
Roč. 9, únor (2018)Number of pages 16 s. Language eng - English Country CH - Switzerland Keywords plasmacytoid dendritic cells ; toll-like receptors 7 and 9 (TLR 7/9) ; B cell-like receptor signaling ; regulatory receptors ; blood dendritic cell antigen 2 ; MEK1/2 ; c-FOS ; type I interferon Subject RIV EB - Genetics ; Molecular Biology OECD category Immunology R&D Projects ED1.1.00/02.0109 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) GA14-32547S GA ČR - Czech Science Foundation (CSF) Institutional support UMG-J - RVO:68378050 UT WOS 000426071700002 DOI 10.3389/fimmu.2018.00364 Annotation Recent studies have reported that the crosslinking of regulatory receptors (RRs), such as blood dendritic cell antigen 2 (BDCA-2) (CD303) or ILT7 (CD85g), of plasmacytoid dendritic cells (pDCs) efficiently suppresses the production of type I interferons (IFN-I, alpha/ss/omega) and other cytokines in response to toll-like receptor 7 and 9 (TLR7/9) ligands. The exact mechanism of how this B cell receptor (BCR)-like signaling blocks TLR7/9-mediated IFN-I production is unknown. Here, we stimulated BCR-like signaling by ligation of RRs with BDCA-2 and ILT7 mAbs, hepatitis C virus particles, or BST2 expressing cells. We compared BCR-like signaling in proliferating pDC cell line GEN2.2 and in primary pDCs from healthy donors, and addressed the question of whether pharmacological targeting of BCR-like signaling can antagonize RR-induced pDC inhibition. To this end, we tested the TLR9-mediated production of IFN-I and pro-inflammatory cytokines in pDCs exposed to a panel of inhibitors of signaling molecules involved in BCR-like, MAPK, NF-kappa B, and calcium signaling pathways. We found that MEK1/2 inhibitors, PD0325901 and U0126 potentiated TLR9-mediated production of IFN-I in GEN2.2 cells. More importantly, MEK1/2 inhibitors significantly increased the TLR9-mediated IFN-I production blocked in both GEN2.2 cells and primary pDCs upon stimulation of BCR-like or phorbol 12-myristate 13-acetate-induced protein kinase C (PKC) signaling. Triggering of BCR-like and PKC signaling in pDCs resulted in an upregulation of the expression and phoshorylation of c-FOS, a downstream gene product of the MEK1/2-ERK pathway. We found that the total level of c-FOS was higher in proliferating GEN2.2 cells than in the resting primary pDCs. The PD0325901-facilitated restoration of the TLR9-mediated IFN-I production correlated with the abrogation of MEK1/2-ERK-c-FOS signaling. These results indicate that the MEK1/2-ERK pathway inhibits TLR9-mediated type I IFN production in pDCs and that pharmacological targeting of MEK1/2-ERK signaling could be a strategy to overcome immunotolerance of pDCs and re-establish their immunogenic activity. Workplace Institute of Molecular Genetics Contact Nikol Škňouřilová, nikol.sknourilova@img.cas.cz, Tel.: 241 063 217 Year of Publishing 2019
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