Muscle amino acid uptake is inhibited during sepsis and endotoxemia. Cytokines, in particular tumor necrosis factor (TNF) and interleukin-1 (IL-1), have been implicated as mediators of metabolic alterations in sepsis and other critical illness. In this study, we examined the effect of TNF and IL-1 on muscle amino acid uptake and tested the hypothesis that cytokine-induced changes in muscle amino acid uptake are mediated by glucocorticoids. Intraperitoneal injection in rats of 100 micrograms per kilogram body weight of human recombinant TNF alpha (rTNF alpha) or rIL-1 alpha resulted, two hours later, in 36 and 24 percent reduction, respectively, of amino acid transport in incubated soleus muscles, determined as intracellular uptake of alpha-aminoisobutyric acid. When rats were treated with the glucocorticoid receptor antagonist RU 38486 (5 milligrams per kilogram of body weight) two hours before cytokine injection, the inhibitory effect on muscle amino acid transport of TNF was blocked, whereas that of IL-1 was unaffected. The present results suggest that TNF and IL-1 may regulate amino acid transport in skeletal muscle and that the effect of TNF, but not that of IL-1, is at least partly mediated by glucocorticoids.