HIF‐dependent induction of adenosine receptor A2b skews human dendritic cells to a Th2‐stimulating phenotype under hypoxia

Abstract

Hypoxia is a common characteristic of many pathological and physiological conditions that can markedly change cellular metabolism and cause the accumulation of extracellular adenosine. Recent studies have shown that adenosine can modulate the function of certain immune cell types through binding with different adenosine receptors. Our previous studies have shown that hypoxia has an effect on the biological activity of dendritic cells (DCs) by inducing their differentiation towards a Th2 polarising phenotype. However, the mechanisms underlying this suppression remain unclear. In this study, we have demonstrated that hypoxic mDCs predominantly express adenosine receptor A2b. The A2b receptor antagonist MRS1754 was able to increase the production of IL-12p70 and TNF-a by hypoxic mDCs and elevate the amount of Th1 cytokine IFN-c production in a mDCs-T-cell co-culture system. We also found that the effect of hypoxia on IL-12p70 production was mediated via increased intracellular cAMP levels through the up-regulation of A2b adenosine receptor and the preferential expression of adenosine A2b receptors in hypoxic mDCs was HIF-1a dependent. Therefore, the hypoxic mDCs could provide a useful tool for researching the function of A2bR in human DCs. Our results offer new insights into understanding the molecular mechanisms underlying the biological activities of DCs in local-tissue hypoxic microenvironments.

Contributions of A2Aand A2Badenosine receptors in coronary flow responses in relation to the KATPchannel using A2Band A2A/2Bdouble-knockout mice

“…Furthermore, HIF-1 has also been suggested to upregulate the expression of A 2B ARs under hypoxic conditions (76). Although the underlying mechanism may not be understood at this time, it seems that this relationship only exists between A 2A ARs and A 2B ARs and not between A 1 ARs or A 3 ARs, since there was no significant difference between the CRCs for 2-chloro-N 6 -cyclopentyladenosine (an A 1 -selective agonist) and 2-chloro-N 6 -(3-iodobenzyl)adenosine-5=-N-methylcarboxamide (an A 3 AR-selective agonist) in A 2A/2B DKO mice compared with WT mice (data not shown).…”

The protective Th1 response in mice is induced in the T-cell zone only three weeks after infection with Leishmania major and not during early T-cell activation

“…One possible reason for this controversy could be that cells were isolated before analysis and re-stimulated in culture with L. major-derived antigen. Despite the valuable information obtained by analyzing isolated cells, this approach bears the possibility that typical features profoundly alter during isolation and re-stimulation [15][16][17].…”

Adenosine 2B Receptor Expression on Cancer Cells Promotes Metastasis

“…A2B receptor is induced by hypoxia and has a broad cellular distribution in tumor microenvironment, including myeloid cells (28). Therefore, we hypothesized that the antimetastatic effect of A2BRi might be dependent on immune cells.…”