Cytokines such as interleukin 1 (IL-1), tumor necrosis factor-alpha (TNF-alpha), and interleukin 6 (IL-6) mediate a variety of host responses to trauma and infection, including skeletal muscle proteolysis. This investigation assesses the influence of damaging eccentric exercise on in vitro production and plasma concentrations of cytokines and their relationship to muscle protein breakdown. In a double-blind placebo-controlled protocol, 21 male subjects took vitamin E supplements (800 IU/day) for 48 days, then ran downhill on an inclined treadmill. Twenty-four hours after this single session of eccentric exercise, endotoxin-induced secretion of IL-1 beta was augmented 154% (P less than 0.01) in cells obtained from the placebo subjects, but no significant exercise-related changes were observed in cells from the vitamin E-supplemented subjects. TNF-alpha secretion was also significantly increased 24 h after exercise, but the response was not inhibited by vitamin E. In contrast, IL-6 secretion did not change after exercise, but dietary vitamin E supplementation significantly reduced IL-6 secretion throughout the 12-day period of observation (P = 0.023). Urinary 3-methylhistidine excretion correlated with mononuclear cell secretion of both IL-1 beta (P less than 0.05) and prostaglandin E2 (P less than 0.05), supporting the concept that these mononuclear cell products contribute to the regulation of muscle proteolysis.