Adenosine Regulation of Neutrophil Function

Sammanfattning: The neutrophil granulocyte is an essential component of the human immune system. When rrricrobes invade the body, the highly motile neutrophils quickly leave the vascular compartment and approach, engulf and kill the intruders by releasing a battery of antimicrobial substances. Adenosine is an endogenous purine nucleoside that is supposed to regulate the inflammatory response, for example, by modulating the activity of neutrophils through occupation of A1 and Az receptors. The aim of the present work was to characterize the effects of adenosine on neutrophil functions, particularly phagocytosis and the production of reactive oxygen species (ROS).Adenosine modulated IgG~mediated phagocytosis in neutrophils in a Ca2+dependent way via stimulatory At and inhibitory Az receptors. The Az receptor~mediated inhibition was associated with an elevation of cAMP, which probably activated protein kinase A (PKA) and thereby interfered with actin dynarrrics and expression of BZ integrins. Production of ROS induced by the chemotactic peptide N~formyl-methionylleucyl~ phenylalanine (fMLP) or IgG~opsonized yeast particles was not affected by occupancy of the At receptor, but was, via a cAMP~dependent mechanism, inhibited by engagement of the A2 receptor. Adenosine also reduced L-selectin-induced production of ROS. The inhibition of ROS production by adenosine was more pronounced during fMLP stimulation than during L~selectin~ and IgG~mediated activation, probably because the latter entailed removal of extracellular adenosine through increased activity of adenosine dearrrinase (ADA).Platelets participate in inflammatory reactions, for instance, by affecting neutrophil actiyity. In the present work, platelets inhibited !MLP~stimulated extracellular generation of ROS by inducing the neutrophils to release adenosine and to form a peripheral actin barrier. In contrast, platelets potentiated IgG~mediated phagocytosis and generation of ROS in neutrophils. This involved engagement of neutrophil Pz receptors by plateletderived ATP and enhanced formation of cortical actin filaments. Expanded ADA activity associated with !gO-stimulation counteracted the inhibitory effects of adenosine accumulated during neutrophil-platelet interaction.In conclusion, this work accentuates the importance of adenosine, both exogenously applied and endogenously formed, as an inflammatory agent modulating the activity of the neutrophil granulocyte.

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