The purine nucleoside adenosine is a biologically active extracellular signaling molecule that is formed at sites of metabolic stress associated trauma and sepsis. Adenosine can bind to one or more of four cell surface receptors (A1, A2A, A2B, and A3) through which it exerts varying immunomodulatory effects. During the previous funding period, we tested the hypothesis that high concentrations of endogenous adenosine contribute to immunosuppression, promote bacterial growth, and worsen mortality in animals with intraabdominal polymicrobial sepsis. Because A2A receptors are generally immunosuppressive, we focused our investigations on the role of these receptors in mediating the immunosuppressive effects of adenosine in sepsis. We have discovered that stimulation of A2A receptors with endogenous adenosine contributes to the mortality of mice subjected to a septic insult. This decreased survival of mice caused by A2A receptor stimulation was tightly associated with a capacity of A2A receptor stimulation to increase bacterial burden, to augment immune cell apoptosis, and to increase production of inflammatory cytokines. Although our studies testing the role of A2A receptors validate the hypothesis that adenosine has potentially lethal immunosuppressive and infection-promoting effects following sepsis, further work performed during the previous cycle suggests that adenosine has a more complex role in the pathophysiology of sepsis. Thus to better understand the complex regulatory pathways of the adenosine receptor system in sepsis, we propose the following highly integrated Specific Aims: Aim 1: Elucidate the effect of global adenosine deficiency in regulating immune responsiveness during sepsis. Aim 2: Elucidate the role and the relative importance of A1, A2B and A3 adenosine receptors in regulating immunity during sepsis. New knowledge about the control of septic immunity by distinct adenosine receptors could lead to the identification of novel pharmacological approaches for ameliorating the course of disease and preventing death in sepsis. Aim 3: Elucidate the receptors and intracellular signaling pathways that mediate the modulatory effects of adenosine on the transcription and secretion of cytokines by macrophages stimulated with Gram-negative and Gram-positive bacteria.