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Interleukin 1 beta, tumor necrosis factor-alpha and interleukin 6 decrease nuclear thyroid hormone receptor capacity
1Medizinische Kernklinik und Poliklinik, Universitäts-Krankenhaus Eppendorf, Hamburg, Germany.
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 [125I]-triiodothyronine; bound and free hormone were separated by filtration. Interleukin 1 beta 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 micrograms/l IL-1 beta, respectively. Interleukin 6 and TNF-alpha significantly reduced receptor capacity only at concentrations of 10 micrograms/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 micrograms/l IL-6 or TNF-alpha, respectively. TR affinity was not altered significantly after stimulation with any of the cytokines.(ABSTRACT TRUNCATED AT 250 WORDS)
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 [125I]-triiodothyronine; bound and free hormone were separated by filtration. Interleukin 1 beta 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 micrograms/l IL-1 beta, respectively. Interleukin 6 and TNF-alpha significantly reduced receptor capacity only at concentrations of 10 micrograms/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 micrograms/l IL-6 or TNF-alpha, respectively. TR affinity was not altered significantly after stimulation with any of the cytokines.(ABSTRACT TRUNCATED AT 250 WORDS)