Adenosine modifies interleukin 6 (IL-6) and tumour necrosis factor (TNF) release from immune tissues. Because adenosine alters endocrine function and endocrine cells secrete cytokines, its effects on IL-6 and TNF release from rat adrenals, ovaries, and anterior pituitaries were compared with its effects on cytokine release from rat peritoneal macrophages. Adenosine increased basal IL-6 release and decreased basal TNF release from adrenal zona glomerulosa and zona fasciculata/reticularis cells. IL-6 and TNF release from zona glomerulosa cells was greater (20x) than that of other adrenal cells. An A2 agonist modified adrenal IL-6 and TNF release at lower concentrations than an A1 agonist. Adenosine augmented adrenal IL-6 release stimulated by endotoxin (LPS), interleukin 1 beta (IL-1 beta), adrenocorticotrophic hormone, and angiotensin II. LPS- and IL-1 beta-stimulated adrenal TNF release was inhibited by adenosine. Adenosine increased IL-6 release and inhibited TNF release from ovarian cells. Anterior pituitary cells released IL-6, but no detectable TNF. Adenosine, via A2 receptors, stimulated IL-6 secretion from these cells. Peritoneal macrophage IL-6 release was increased and TNF release decreased by adenosine. Thus, in immune and endocrine tissues, adenosine increases IL-6 release, but inhibits TNF release.