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

Immunol Cell Biol. 2010 Feb;88(2):165-71. doi: 10.1038/icb.2009.77. Epub 2009 Oct 20.


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-alpha by hypoxic mDCs and elevate the amount of Th1 cytokine IFN-gamma 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-1 alpha 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine A2 Receptor Antagonists
  • Cell Differentiation / drug effects
  • Cell Hypoxia / drug effects
  • Cell Hypoxia / immunology
  • Cell Polarity / drug effects
  • Cyclic AMP / metabolism
  • Cytokines / biosynthesis
  • Dendritic Cells / cytology*
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology*
  • Gene Knockdown Techniques
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Interleukin-12 / biosynthesis
  • Intracellular Space / drug effects
  • Intracellular Space / metabolism
  • Lipopolysaccharides / pharmacology
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology*
  • Phenotype
  • Receptor, Adenosine A1 / genetics
  • Receptor, Adenosine A1 / metabolism
  • Receptor, Adenosine A2A / genetics
  • Receptor, Adenosine A2A / metabolism
  • Receptor, Adenosine A2B / genetics
  • Receptor, Adenosine A2B / metabolism*
  • Receptor, Adenosine A3 / genetics
  • Receptor, Adenosine A3 / metabolism
  • Th2 Cells / cytology*
  • Th2 Cells / drug effects
  • Th2 Cells / immunology*


  • Adenosine A2 Receptor Antagonists
  • Cytokines
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Lipopolysaccharides
  • Receptor, Adenosine A1
  • Receptor, Adenosine A2A
  • Receptor, Adenosine A2B
  • Receptor, Adenosine A3
  • Interleukin-12
  • Cyclic AMP