A2a Adenosine Receptors Limit Inflammatory Responses

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A2a Adenosine Receptors Limit Inflammatory Responses

http://rheumatology.medscape.com/reuters/prof/2001/12/12.24/20011221scie004.html

NEW YORK (Reuters Health) Dec 21 - A2a adenosine receptors on T cells and cells of the innate immune system are responsible for downregulation of inflammation, according to investigators at the National Institute of Allergy and Infectious Diseases. Drs. Aklo Ohta and Michail Sitkovsky, in Bethesda, land, began their investigation by inducing inflammatory liver injury in mice using concanavalin A. As reported in Nature for December 20/27, an A2a adenosine receptor agonist prevented the liver damage and inhibited cytokine production by activated macrophages and T cells in vitro. When A2a adenosine receptors were genetically inactivated, liver damage from concanavalin A was so severe that two of four mutant mice, but not wild-type mice, died within 8 hours. Secretion of pro-inflammatory cytokines was increased in intensity and duration. Even low doses caused severe tissue damage in mutant mice and only minimal or no liver damage in control mice. The NIAID investigators confirmed the protective effects of A2a receptors in models of inflammatory liver injury and system inflammation that involved Pseudomonas aeruginosa exotoxin a, carbon tetrachloride, and an in vivo septic shock model using bacterial endotoxins. Dr. Sitkovsky noted in an interview with Reuters Health that sulfasalazine and methotrexate, drugs known to be effective in the treatment of rheumatoid arthritis but for which the pathway previously had not been elucidated, reduce inflammation in rheumatoid arthritis by employing the A2a adenosine pathway. Researchers should also evaluate the potential role of modulating the A2a adenosine pathway to enhance inflammatory responses in immunosuppressed patients or for damaging cancer tissue, Dr. Sitkovsky added. Nature 2001;414:916-920.