INTERLEUKIN-1-BETA, TUMOR-NECROSIS-FACTOR-ALPHA AND INTERLEUKIN-6 DECREASE NUCLEAR THYROID-HORMONE RECEPTOR CAPACITY IN A LIVER-CELL LINE

Many of the acute inflammatory responses in critical illness are mediated by tumor necrosis factor-alpha (TNF-alpha), interleukin 1 beta (IL-1 beta) and interleukin 6 (IL-6). Furthermore, these cytokines are involved in mediating the characteristic changes of thyroid function during acute disease known as non-thyroidal illness. In the present studies we investigated in vitro whether TNF-alpha, IL-1 beta and IL-6 modify nuclear thyroid hormone receptor (TR) capacity and/or affinity. Regulation of TR synthesis was studied in the human hepatoma cell line Hep-G2. Subconfluent cells were incubated with recombinant cytokines in serum-free medium. Nuclear extracts were prepared by high-salt extraction of cell nuclei. Binding assays were performed with [I-125]-triiodothyronine; bound and free hormone were separated by filtration. Interleukin Ip decreased TR capacity in a dose-dependent manner. Compared with unstimulated cells, the TR capacity was reduced to 87.9 +/- 3.9% (p < 0.05), 80.1 +/- 3.9% (p < 0.01) and 72.1 +/- 5.1% (p < 0.01) after incubation with 0.1, 1.0 and 100 mu g/l IL-1 beta, respectively. Interleukin 6 and TNF-alpha significantly reduced receptor capacity only at concentrations of 10 mu g/l or higher and the magnitude of the reduction was lower than with IL-1 beta. The TR capacity was reduced to 81.2 +/- 2.3% (p < 0.01) and 83.2 +/- 6.6% (p < 0.05) after stimulation with 10 mu g/l IL-6 or TNF-alpha, respectively. TR affinity was not altered significantly after stimulation with any of the cytokines. In conclusion, we present evidence that the capacity of hepatic nuclear TRs is regulated by IL-1 beta, IL-6 and TNF-alpha. As cellular reaction to thyroid hormone stimulation depends on the number of nuclear TRs, this mechanism mag serve to restrict catabolic effects of thyroid hormones during acute illness.