Adenosine: a physiological modulator of superoxide anion generation by human neutrophils.

Abstract

The responses of neutrophils to soluble and insoluble stimuli include aggregation, chemotaxis, lysosomal enzyme release, and the generation of active oxygen species such as superoxide anion. These processes, which have been described as stimulus-response coupling, can be influenced by ions, cyclic nucleotides, and metabolites of arachidonate (1) . In recent years, a role for adenosine has been described in the stimulus-response coupling of a variety of cells and tissues. Adenosine receptors and/or hormone like responses to adenosine have been reported in adipocytes, neurons, hepatocytes, smooth muscle cells, coronary arteries, and heart muscle (2-7). These responses have also been described in circulating cells of the blood, i.e., lymphocytes (8-10), macrophages (11), basophils (12), and mast cells (13).Adenosine in the presence of homocysteine thiolactone inhibits transmethylation reactions. These reactions are required for maintenance of high avidity receptors for the chemoattractant N-formyl-methionyl-leucyl-phenylalanine (FMLP)t on murine macrophages. Pike and Snyderman (11) found that generation of superoxide anion by macrophages in response to FMLP was inhibited by adenosine. These studies suggested that adenosine might regulate stimulusresponse coupling in neutrophils as well. However, Marone et al. (14) were unable to demonstrate a significant effect of adenosine on the release of lysosomal enzyme (beta-glucuronidase) from human neutrophils stimulated by particle ingestion.We have therefore examined the role of adenosine as a modulator of superoxide anion generation, degranulation, and aggregation in human neutrophils exposed to soluble stimulants. We report that adenosine, at physiological concentrations, is a potent and specific regulator of neutrophil superoxide anion generation but exerts little or no effect on either degranulation or aggregation. Further, we demonstrate that this effect is independent of the cellular uptake of

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“…Adenosine is a modulator of the immune response through interactions with surface receptors of polymorphonuclear leukocytes (PMNL), monocytes, macrophages, and endothelial cells, among cellular targets [4,18,31,41]. Binding of adenosine or selective agonists through the AZA receptor induces an anti-inflammatory response likely through a cyclic adenosine monophosphate (CAMP) dependent pathway [41].…”

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“…Subsequent pharmacological studies from our laboratory [13] and others [14] revealed that the effects of adenosine were mediated by interaction with a specific cell surface receptor (formerly the A 2 receptor, now clearly identified as the A 2A receptor). That endogenously released adenosine could diminish inflammation was first demonstrated in our studies of neutrophils [12] and later confirmed in our laboratory using a model of neutrophil-mediated vascular injury [15]. Rosengren and colleagues first reported that endogenously generated adenosine acting at its receptors exercised a tonic suppressive effect on inflammation in vivo [16], and Ohta and Sitkovsky [17] expanded on this finding by identifying adenosine, acting at A 2A receptors, as the endogenous signal terminating acute inflammation in several models of inflammation.…”

“…The anti-inflammatory effects of adenosine were first suggested by our observation that adenosine, acting at a site on the surface of the neutrophil, inhibits stimulated neutrophil generation of superoxide anion [12]. Subsequent pharmacological studies from our laboratory [13] and others [14] revealed that the effects of adenosine were mediated by interaction with a specific cell surface receptor (formerly the A 2 receptor, now clearly identified as the A 2A receptor).…”

“…Adenosine, via inter-action with A 2A receptors, inhibits stimulated neutrophil adhesion, generation of toxic oxygen metabolites, phagocytosis, and neutrophil-mediated cell injury [7, 12, 13, 22]. Adenosine, most likely acting at A 2A receptors, also inhibits lymphocyte proliferation and induces suppressor function and phenotype [23–34].…”

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“…Un changement phénotypique L'adénosine inhibe l'adhérence des PN à la paroi endothéliale [22], ainsi que l'explosion oxydative et la dégranulation [23]. L'activation du récepteur A 2A par ce nucléoside provoque un changement majeur dans le profil de sécrétion des médiateurs lipidiques par les PN (Figure 2).…”