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NFκB- and MAP-Kinase Signaling Contribute to the Activation of Murine Myeloid Dendritic Cells by a Flagellin A: Allergen Fusion Protein

Paul-Ehrlich-Institut, Vice President´s Research Group 1: Molecular Allergology, 63225 Langen, Hesse, Germany
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Cells 2019, 8(4), 355; https://doi.org/10.3390/cells8040355
Received: 12 December 2018 / Revised: 26 March 2019 / Accepted: 12 April 2019 / Published: 15 April 2019
(This article belongs to the Special Issue The Molecular and Cellular Basis for Allergies & Asthma)
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Abstract

Fusion proteins incorporating the TLR5-ligand flagellin are currently undergoing clinical trials as vaccine candidates for many diseases. We recently reported a flagellin:allergen fusion protein containing the TLR5-ligand flagellin A (FlaA) from Listeria monocytogenes and the major birch pollen allergen Bet v 1 (rFlaA:Betv1) to prevent allergic sensitization in an experimental mouse model. This study analyzes the signaling pathways contributing to rFlaA:Betv1-mediated pro- and anti-inflammatory cytokine secretion and cell metabolism in myeloid dendritic cells (mDCs) in vitro. The influence of mammalian target of rapamycin (mTOR)-, NFκB-, and MAP kinase (MAPK)-signaling on cytokine secretion and metabolic activity of bone marrow (BM)-derived mDCs stimulated with rFlaA:Betv1 were investigated by pre-treatment with either mTOR- (rapamycin), NFκB- (dexamethason, BMS-345541, TPCA-1, triptolide, or BAY-11) or MAPK- (SP600125, U0126, or SB202190) inhibitors, respectively. rFlaA:Betv1-mediated IL-10 secretion as well as activation of mDC metabolism, rather than pro-inflammatory cytokine secretion, were inhibited by rapamycin. Inhibition of NFκB-signaling suppressed rFlaA:Betv1-induced IL-12, while inhibition of MAPK-signaling dose-dependently suppressed rFlaA:Betv1-induced IL-10 as well as pro-inflammatory IL-6 and TNF-α production. Notably, with the exception of a partial JNK-dependency, rFlaA:Betv1-mediated effects on mDC metabolism were mostly NFκB- and MAPK-independent. Therefore, MAPK-mediated activation of both NFκB- and mTOR-signaling likely is a key pathway for the production of pro- and anti-inflammatory cytokines by flagellin fusion protein vaccines. View Full-Text
Keywords: flagellin; TLR5; Bet v 1; birch allergy; vaccine; fusion protein; metabolism; MAPK; NFκB; signalling flagellin; TLR5; Bet v 1; birch allergy; vaccine; fusion protein; metabolism; MAPK; NFκB; signalling
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Moeller, T.; Wolfheimer, S.; Goretzki, A.; Scheurer, S.; Schülke, S. NFκB- and MAP-Kinase Signaling Contribute to the Activation of Murine Myeloid Dendritic Cells by a Flagellin A: Allergen Fusion Protein. Cells 2019, 8, 355.

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