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Biotech / Medical : Cadus Pharmaceutical Corp. (KDUS) -- Ignore unavailable to you. Want to Upgrade?

To: scaram(o)uche who wrote (711)	1/25/2002 6:58:27 PM
From: scaram(o)uche	Read Replies (1) \| Respond to of 1833

nature.com Nature Reviews Drug Discovery 1, (2002) G-PROTEIN-COUPLED RECEPTORS Putting the brake on inflammation Peter Kirkpatrick Chronic or inappropriate inflammation is characteristic of many disorders, such as rheumatoid arthritis and asthma. Although many drugs can reduce inflammation, current treatments merely ameliorate these diseases, a reflection of the fact that the body's own mechanism for controlling inflammation and the accompanying tissue damage is poorly understood. Now, writing in Nature, Akio Ohta and Michail Sitkovsky report that A2A adenosine receptors are crucially involved in the limitation and termination of inflammatory responses. Noting that extracellular adenosine accumulates in inflamed and damaged tissues, and the immunosuppressive properties of adenosine A2A receptors on immune cells, the authors hypothesized that adenosine acting at the A2A receptor could be the key signal that limits inflammation. To test this theory, they used mice deficient for the A2A receptor, and exposed them to concanavalin A, which is a well-characterized inducer of inflammatory tissue damage in the liver, with the damage being mediated by T cells, macrophages and pro-inflammatory cytokines, such as tumour-necrosis factor (TNF)- and interferon (IFN)-. The receptor-deficient mice all showed extensive tissue damage, and some died, in contrast to normal mice exposed to the same inflammatory stimulus, which only showed minimal tissue damage or were unaffected. Moreover, excessive and prolonged accumulation of TNF- and IFN- was observed in the serum of the receptor-deficient mice, but not in that of normal mice. Ohta and Sitkovsky further confirmed the tissue-protecting properties of A2A receptors in other models of inflammatory damage and systemic inflammation. The striking phenotypes observed in all the experiments indicate that no other mechanism for limiting inflammation can compensate fully for the loss of A2A receptors on immune cells. Before this report, A2A receptors were just one of many candidates for the role of damping inflammation to prevent excessive tissue damage in vivo; other Gs-protein-coupled receptors were known to block inflammation when activated pharmacologically. The demonstration of the physiological role of A2A receptors in the downregulation of acute inflammation is a key conceptual advance that could stimulate the development of novel therapeutic approaches for controlling excessive inflammation. Furthermore, modulation of A2A receptors could be a new strategy for enhancing inflammatory responses when desirable; for example, to improve the immune defence in immunosuppressed patients or to increase inflammatory damage to cancer tissue.