Adenosine receptor signaling targets both PKA and epac pathways to polarize dendritic cells to a suppressive phenotype

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buir.contributor.authorKayhan, Merve
buir.contributor.authorKoyaş, Altay
buir.contributor.authorAkdemir, İmran
buir.contributor.authorSavaş, Ali Can
buir.contributor.authorÇekiç, Çağlar
dc.citation.epage3255en_US
dc.citation.issueNumber12en_US
dc.citation.spage3247en_US
dc.citation.volumeNumber203en_US
dc.contributor.authorKayhan, Merveen_US
dc.contributor.authorKoyaş, Altayen_US
dc.contributor.authorAkdemir, İmranen_US
dc.contributor.authorSavaş, Ali Canen_US
dc.contributor.authorÇekiç, Çağlaren_US
dc.date.accessioned2020-02-14T07:54:35Z
dc.date.available2020-02-14T07:54:35Z
dc.date.issued2019
dc.departmentDepartment of Molecular Biology and Geneticsen_US
dc.description.abstractExtracellular adenosine accumulates in tumors and causes suppression of immune cells. Suppressive adenosine signaling is achieved through adenosine A2A and A2B receptors, which are Gs coupled, and their activation elevates cAMP levels. Gs-coupled GPCR signaling causes cAMP accumulation, which plays an anti-inflammatory role in immune cells. Protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac) are two intracellular receptors of cAMP. In this study we showed that adenosine receptor signaling polarizes activated murine dendritic cells (DCs) into a tumor-promoting suppressive phenotype. Adenosine receptor signaling activates cAMP pathway and upregulates the negative regulators of NF-κB but does not influence phosphorylation of immediate inflammatory signaling molecules downstream of TLR signaling. Pharmacologic activation of both PKA and Epac pathways by specific cAMP analogues phenocopied the effects of adenosine signaling on murine DCs, such as suppression of proinflammatory cytokines, elevation of anti-inflammatory IL-10, increased expression of regulators of NF-κB pathway, and finally suppression of T cell activation. Inhibition of effector cytokine, IL-12p40 production, and increased immunosuppressive IL-10 production by adenosine signaling is significantly reversed only when both PKA and Epac pathways were inhibited together. Adenosine signaling increased IL-10 secretion while decreasing IL-12p40 secretion in human monocyte-derived DCs. Stimulation of both PKA and Epac pathways also caused combinatorial effects in regulation of IL-12p40 secretion in human monocyte-derived DCs. Interestingly, PKA signaling alone caused similar increase in IL-10 secretion to that of adenosine signaling in human monocyte-derived DCs. Our data suggest adenosine/cAMP signaling targets both PKA/Epac pathways to fully differentiate DCs into a suppressive phenotype.en_US
dc.identifier.doi10.4049/jimmunol.1900765en_US
dc.identifier.issn0022-1767
dc.identifier.urihttp://hdl.handle.net/11693/53351
dc.language.isoEnglishen_US
dc.publisherAmerican Association of Immunologistsen_US
dc.relation.isversionofhttps://dx.doi.org/10.4049/jimmunol.1900765en_US
dc.source.titleJournal of Immunologyen_US
dc.titleAdenosine receptor signaling targets both PKA and epac pathways to polarize dendritic cells to a suppressive phenotypeen_US
dc.typeArticleen_US
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