Gs-coupled Adenosine Receptors Differentially Limit Antigen-Induced Mast Cell Activation

J Pharmacol Exp Ther. 2013 Feb;344(2):426-35. doi: 10.1124/jpet.112.198978. Epub 2012 Nov 13.

Abstract

Mast cell activation results in the immediate release of proinflammatory mediators prestored in cytoplasmic granules, as well as initiation of lipid mediator production and cytokine synthesis by these resident tissue leukocytes. Allergen-induced mast cell activation is central to the pathogenesis of asthma and other allergic diseases. Presently, most pharmacological agents for the treatment of allergic disease target receptors for inflammatory mediators. Many of these mediators, such as histamine, are released by mast cells. Targeting pathways that limit antigen-induced mast cell activation may have greater therapeutic efficacy by inhibiting the synthesis and release of many proinflammatory mediators produced in the mast cell. In vitro studies using cultured human and mouse mast cells, and studies of mice lacking A(2B) receptors, suggest that adenosine receptors, specifically the G(s)-coupled A(2A) and A(2B) receptors, might provide such a target. Here, using a panel of mice lacking various combinations of adenosine receptors, and mast cells derived from these animals, we show that adenosine receptor agonists provide an effective means of inhibition of mast cell degranulation and induction of cytokine production both in vitro and in vivo. We identify A(2B) as the primary receptor limiting mast cell degranulation, whereas the combined activity of A(2A) and A(2B) is required for the inhibition of cytokine synthesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine A2 Receptor Agonists / pharmacology*
  • Animals
  • Antigens / pharmacology
  • Cell Degranulation / drug effects
  • Cells, Cultured
  • Cytokines / metabolism
  • Cytoplasmic Granules / drug effects
  • Cytoplasmic Granules / immunology
  • Cytoplasmic Granules / metabolism
  • Dinitrophenols / pharmacology
  • Female
  • GTP-Binding Protein alpha Subunits, Gs / genetics
  • GTP-Binding Protein alpha Subunits, Gs / metabolism*
  • Male
  • Mast Cells / drug effects*
  • Mast Cells / immunology
  • Mast Cells / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Passive Cutaneous Anaphylaxis / immunology
  • Receptor, Adenosine A2A / genetics
  • Receptor, Adenosine A2A / metabolism*
  • Receptor, Adenosine A2B / genetics
  • Receptor, Adenosine A2B / metabolism*
  • Serum Albumin / pharmacology

Substances

  • Adenosine A2 Receptor Agonists
  • Antigens
  • Cytokines
  • Dinitrophenols
  • Receptor, Adenosine A2A
  • Receptor, Adenosine A2B
  • Serum Albumin
  • dinitrophenyl-human serum albumin conjugate
  • GTP-Binding Protein alpha Subunits, Gs