Role of cytokines in the modulation of nitric oxide production by cyclic AMP.
Enhanced levels of cyclic AMP (cAMP), resulting from stimulation of adenylyl cyclase through activation of distinct pharmacological receptor systems, have a remarkable impact on the activity of the immune system. Among other responses, production of nitric oxide (NO) is also affected. The effects of cAMP range from stimulation to inhibition (or no effect) of immune-stimulated biosynthesis of NO, with a preponderance of stimulatory interference. cAMP has been shown to be a potent, dual modulator of cytokine expression. It dose-dependently suppresses secretion of major NO up-regulatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma). On the other hand, production of IL-10, which is known to regulate the inducible NO synthase (iNOS) activation in both a positive and negative direction, is inversely enhanced. It is suggested that the dual effects of cAMP on NO formation are likely to result from the differences in the concentration ratio of these cytokines. The value of this parameter depends on the type and concentration of cAMP-stable derivatives and cAMP-enhancing agents, such as prostaglandins, beta-adrenoceptor agonists, phosphodiesterase inhibitors, forskolin and cholera toxin. The cytokine ratio may be influenced by dynamically developing multiple down- and up-regulatory feedback circuits among cytokines, NO, and cAMP.
Laboratory of Molecular Immunopharmacology, Institute of Pharmacology, Academy of Sciences, Vídenská 1083, 14220 Prague, Czech Republic. zidekz@biomed.cas.cz
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Zídek
D000241:Adenosine / Q000502:physiology; D000818:Animals; D000242:Cyclic AMP / Q000502:physiology*; D016207:Cytokines / Q000502:physiology*; D009569:Nitric Oxide / Q000096:biosynthesis*
D016207:Cytokines; D009569:Nitric Oxide; D000242:Cyclic AMP; D000241:Adenosine