Journal of Molecular Medicine

, Volume 91, Issue 2, pp 183–193

Transcriptional control of adenosine signaling by hypoxia-inducible transcription factors during ischemic or inflammatory disease

  • Jens M. Poth
  • Kelley Brodsky
  • Heidi Ehrentraut
  • Almut Grenz
  • Holger K. Eltzschig
Review

Abstract

Inflammatory lesions, ischemic tissues, or solid tumors are characterized by the occurrence of severe tissue hypoxia within the diseased tissue. Subsequent stabilization of hypoxia-inducible transcription factors—particularly of hypoxia-inducible factor 1α (HIF1A)—results in significant alterations of gene expression of resident cells or inflammatory cells that have been recruited into such lesions. Interestingly, studies of hypoxia-induced changes of gene expression identified a transcriptional program that promotes extracellular adenosine signaling. Adenosine is a signaling molecule that functions through the activation of four distinct adenosine receptors—the ADORA1, ADORA2A, ADORA2B, and ADORA3 receptors. Extracellular adenosine is predominantly derived from the phosphohydrolysis of precursor nucleotides, such as adenosine triphosphate or adenosine monophosphate. HIF1A-elicited alterations in gene expression enhance the enzymatic capacity within inflamed tissues to produce extracellular adenosine. Moreover, hypoxia-elicited induction of adenosine receptors—particularly of ADORA2B—results in increased signal transduction. Functional studies in genetic models for HIF1A or adenosine receptors implicate this pathway in an endogenous feedback loop that dampens excessive inflammation and promotes injury resolution, while at the same time enhancing ischemia tolerance. Therefore, pharmacological strategies to enhance HIF-elicited adenosine production or to promote adenosine signaling through adenosine receptors are being investigated for the treatment of acute inflammatory or ischemic diseases characterized by tissue hypoxia.

Keywords

Adenosine A1 A2A A2B A3 Ischemia Cancer Hypoxia-inducible factor HIF1 HIF2 Equilibrative nucleoside transporters ENT1 ENT2 Adenosine kinase Adenosine deaminase CD73 Ectonucleotidase CD39 Apyrase AMP ATP Acute lung injury Colitis Inflammatory bowel disease Ischemia Sepsis 

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Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Jens M. Poth
    • 1
    • 2
  • Kelley Brodsky
    • 1
  • Heidi Ehrentraut
    • 1
    • 2
  • Almut Grenz
    • 1
  • Holger K. Eltzschig
    • 1
  1. 1.Mucosal Inflammation Program, Department of AnesthesiologyUniversity of Colorado School of MedicineAuroraUSA
  2. 2.Department of Anesthesiology and Intensive Care MedicineUniversity Hospital BonnBonnGermany

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