TLR-Induced IL-12 and CCL2 Production by Myeloid Cells Is Dependent on Adenosine A(3) Receptor-Mediated Signaling
Autor: | Dimitri A. Diavatopoulos, Ella A. Zuiderwijk-Sick, Elles Simonetti, Hans J. P. M. Koenen, Céline van der Putten, Sacha A. F. T. van Hijum, Jeffrey J. Bajramovic, Ad P. IJzerman, Lejla Sukurova, Johannes M. van Noort, Saskia M. Burm, Jennifer Veth |
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Rok vydání: | 2019 |
Předmět: |
Innate immune system
Chemistry Immunology lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] Adenosine A3 receptor Adenosine Adenosine receptor Cell biology 03 medical and health sciences TLR2 Paracrine signalling All institutes and research themes of the Radboud University Medical Center 0302 clinical medicine medicine Immunology and Allergy Phosphorylation Autocrine signalling Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5] 030215 immunology medicine.drug |
Zdroj: | Journal of Immunology, 202, 2421-2430 Journal of Immunology, 202, 8, pp. 2421-2430 |
ISSN: | 0022-1767 |
Popis: | TLR-induced signaling potently activates cells of the innate immune system and is subject to regulation at different levels. Inflammatory conditions are associated with increased levels of extracellular adenosine, which can modulate TLR-induced production of cytokines through adenosine receptor–mediated signaling. There are four adenosine receptor subtypes that induce different signaling cascades. In this study, we demonstrate a pivotal contribution of adenosine A3 receptor (A3R)–mediated signaling to the TLR4-induced expression of IL-12 in different types of human myeloid APC. In dendritic cells, IL-12 and CCL2 responses as evoked by TLR2, 3, 4, 5, and 8, as well as IL-12 responses evoked by whole pathogens, were all reduced when A3R-mediated signaling was blocked. As a result, concomitant production of IFN-γ and IL-17 by T cells was significantly inhibited. We further show that selective inhibition of A3R-mediated signaling reduced TLR-induced phosphorylation of the transcription factor STAT1 at tyrosine 701. Next-generation sequencing revealed that A3R-mediated signaling controls the expression of metallothioneins, known inhibitors of STAT1 phosphorylation. Together our results reveal a novel regulatory layer of innate immune responses, with a central role for metallothioneins and autocrine/paracrine signaling via A3Rs. |
Databáze: | OpenAIRE |
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