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Biochem Pharmacol. 2003 Feb 15;65(4):493-501.

Use of the A(2A) adenosine receptor as a physiological immunosuppressor and to engineer inflammation in vivo.

Author information

1
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1892, USA. mvsitkov@helix.nih.gov

Abstract

Inflammation must be inhibited in order to treat, e.g., sepsis or autoimmune diseases or must be selectively enhanced to improve, for example, immunotherapies of tumors or the development of vaccines. Predictable enhancement of inflammation depends upon the knowledge of the "natural" pathways by which it is down-regulated in vivo. Extracellular adenosine and A(2A) adenosine (purinergic) receptors were identified recently as anti-inflammatory signals and as sensors of excessive inflammatory tissue damage, respectively (Ohta A and Sitkovsky M, Nature 2001;414:916-20). These molecules may function as an important part of a physiological "metabolic switch" mechanism, whereby the inflammatory stimuli-produced local tissue damage and hypoxia cause adenosine accumulation and signaling through cyclic AMP-elevating A(2A) adenosine receptors in a delayed negative feedback manner. Patterns of A(2A) receptor expression are activation- and differentiation-dependent, thereby allowing for the "acquisition" of an immunosuppressive "OFF button" and creation of a time-window for immunomodulation. Identification of A(2A) adenosine receptors as "natural" brakes of inflammation provided a useful framework for understanding how tissues regulate inflammation and how to enhance or decrease (engineer) inflammation by targeting this endogenous anti-inflammatory pathway. These findings point to the need of more detailed testing of anti-inflammatory agonists of A(2A) receptors and create a previously unrecognized strategy to enhance inflammation and targeted tissue damage by using antagonists of A(2A) receptors. It is important to further identify the contributions of different types of immune cells at different stages of the inflammatory processes in different tissues to enable the "tailored" treatments with drugs that modulate the signaling through A(2A) purinergic receptors.

PMID:
12566076
[Indexed for MEDLINE]

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