The etiology of the prompt decline in serum T(3) in patients with nonthyroidal illness syndrome has not been adequately explained. It has been attributed to various parameters, including test artifacts, inhibitors of T(4) and T(3) binding to proteins, decreased 5'-deiodinase activity, and circulating cytokines. Currently, much attention is centered on the role of IL-6 and TNFalpha in developing the nonthyroidal illness syndrome through an effect on the hypothalamus, pituitary, and possibly 5'-deiodinase activity. We therefore studied the relation of the endogenous serum IL-6 and TNFalpha rise early in the course of nonthyroidal illness syndrome to the early decline in serum T(3) in 19 apparently healthy individuals, aged 43 +/- 16 yr, who underwent elective abdominal surgery for cholelithiasis or gastroplasty. Serum T(3), free T(3), T(4), free T(4), rT(3), TSH, IL-6, and TNFalpha were measured before and at various time intervals up to 42 h after skin incision. We observed a prompt decline in serum T(3) 30 min before skin incision, which continued to decline throughout the observational period. The magnitude of the decline reached 20% from the baseline value at 2 h. The early decline of T(3) was attenuated and lasted from the 2-8 h, probably due to the sharp increase in serum TSH that started immediately after the entrance to the operating room and lasted for 2 h. In contrast, serum T(4) and free T(4) concentrations were increased soon after skin incision and remained elevated during the first postoperative day. Serum rT(3) increased approximately 6 h after the initiation of surgery and remained elevated thereafter. Serum IL-6 remained essentially undetectable for 2 h after skin incision, whereas serum T(3) was low. Two hours after skin incision, serum IL-6 increased sharply and remained elevated throughout the observational period. Serum TNFalpha remained essentially undetectable throughout the postoperative period. Serum cortisol increased rapidly upon entrance to the operating room and remained elevated throughout the postoperative period. We conclude that the decline in serum T(3) early in the course of nonthyroidal illness syndrome is not due to increased serum IL-6 or TNFalpha levels. The brisk TSH secretion soon after the onset of the syndrome attenuates the decline in serum T(3) due to T(3) secretion from the thyroid. The early and brisk cortisol response to surgery may at least in part explain the early decrease in serum T(3) in nonthyroidal illness syndrome.