Cytokines, such as tumor necrosis factor-alpha and interleukin-1 beta (IL-1 beta), alter thyroid hormone metabolism, and may be involved in the pathogenesis of the euthyroid sick syndrome. Both cytokines also induce the production of IL-6. To assess whether IL-6 itself modulates thyroid hormone metabolism, we studied the acute and chronic effects of recombinant human IL-6 (rhIL-6) on thyroid hormone concentrations in patients with renal cell cancer. In the first study protocol, plasma thyroid hormone concentrations were measured during a 4-h infusion of rhIL-6 (150 micrograms) or, on another day, during infusion of saline (control; n = 8). There were no effects of rhIL-6 infusion on T4, free T4, or thyroid hormone-binding index. However, rhIL-6 induced a significant decrease in the plasma concentrations of TSH (P < 0.001) and T3 (P < 0.001) compared with those in the control study, associated with an increase in rT3 concentrations (P < 0.001). In the second study, a dose of 150 micrograms rhIL-6 was administered sc for 42 consecutive days (n = 8). Weekly assessment of thyroid hormone and TSH concentrations showed a decrease in the T3 concentration (P < 0.001) and a transient increase in rT3 (P < 0.01) and free T4 concentrations (P < 0.01). There were no changes in T4 concentrations during chronic administration of rhIL-6. It is concluded that IL-6 induces major changes in thyroid hormone metabolism and may be another pathogenetic factor in the euthyroid sick syndrome.