Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage

Nature. 2001 Dec 20-27;414(6866):916-20. doi: 10.1038/414916a.

Abstract

Inappropriate or prolonged inflammation is the main cause of many diseases; for this reason it is important to understand the physiological mechanisms that terminate inflammation in vivo. Agonists for several Gs-protein-coupled receptors, including cell-surface adenosine purinergic receptors, can increase levels of immunosuppressive cyclic AMP in immune cells; however, it was unknown whether any of these receptors regulates inflammation in vivo. Here we show that A2a adenosine receptors have a non-redundant role in the attenuation of inflammation and tissue damage in vivo. Sub-threshold doses of an inflammatory stimulus that caused minimal tissue damage in wild-type mice were sufficient to induce extensive tissue damage, more prolonged and higher levels of pro-inflammatory cytokines, and death of male animals deficient in the A2a adenosine receptor. Similar observations were made in studies of three different models of inflammation and liver damage as well as during bacterial endotoxin-induced septic shock. We suggest that A2a adenosine receptors are a critical part of the physiological negative feedback mechanism for limitation and termination of both tissue-specific and systemic inflammatory responses.

MeSH terms

  • Adenosine / metabolism
  • Animals
  • Chemical and Drug Induced Liver Injury
  • Concanavalin A
  • Cytokines / metabolism
  • GTP-Binding Proteins / metabolism
  • Inflammation / etiology
  • Inflammation / metabolism*
  • Inflammation Mediators / metabolism*
  • Liver / pathology
  • Liver Diseases / metabolism
  • Liver Diseases / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Phenotype
  • Receptors, Purinergic P1 / genetics
  • Receptors, Purinergic P1 / physiology*
  • Shock, Septic / metabolism
  • Shock, Septic / pathology
  • T-Lymphocytes / immunology

Substances

  • Cytokines
  • Inflammation Mediators
  • Receptors, Purinergic P1
  • Concanavalin A
  • GTP-Binding Proteins
  • Adenosine