Tumor necrosis factor (TNF), a peptide produced by macrophages in response to endotoxin, has been implicated as a mediator of septic shock. This study examined the effects of injections of recombinant (r) human TNF on circulating levels of metabolic substrates and hormones in conscious, unrestrained rats and the effects of TNF on cortisol secretion from human adrenocortical cells in vitro. Sublethal doses of rTNF--doses that did not produce hemodynamic changes in previous work--produced rapid (1 hour), significant increases in blood levels of glucose, lactate, and triglycerides and decreases in plasma levels of branched chain amino acids. Plasma levels of glucagon, corticosterone, ACTH, norepinephrine, and dihydroxyphenylglycol were also increased significantly. Incubation of adrenocortical cells with either 0.15 or 1.5 micrograms of rTNF increased cortisol secretion to the same extent as did 10(-10) mol/L ACTH. Administration of TNF produces a variety of metabolic and neuroendocrine effects including stimulation of anterior pituitary, adrenal cortical, and pancreatic secretion, and sympathoneural activation. These changes, and the in vitro results, are consistent with the view that immune cells can interact with endocrine cells through release of TNF.