Ongphiphadhanakul B, Fang SL, Tang K-T, Patwardhan NA, Braverman LE. Tumor necrosis factor-α decreases thyrotropin-induced 5′-deiodinase activity in FRTL-5 thyroid cells. Eur J Endocrinol 1994;130:502–7. ISSN 0804–4643
Tumor necrosis factor-α (TNF-α) exerts various effects on many cell types. Acute administration of TNF-α to rats decreases hepatic 5′-deiodinase activity (5′D-I) and TNF-α has been implicated in the pathogenesis of the low triiodothyronine syndrome in non-thyroidal illness in humans. The thyroid, liver and kidney are rich in 5′D-I. Unlike hepatic and renal 5′D-I, thyroid 5′D-I is regulated by thyrotropin. We have investigated the effects of TNF-α on 5D-I in FRTL-5 cells, a cultured rat thyroid follicular cell line. Tumor necrosis factor-α did not significantly affect basal 5′D-I but thyrotropin markedly increased 5′D-I (p < 0.001). This TSH-induced increase in 5′D-I was attenuated by TNF-α in a dose-dependent manner (p < 0.001). Enzyme kinetic analysis demonstrated that thyrotropin increased 5′D-I by increasing Vmax (p < 0.01) without significantly affecting Km. Likewise, TNF-α decreased the thyrotropin-induced 5′D-I by decreasing Vmax (p < 0.05) but not Km. The effect of TNF-α on thyrotropin-induced 5′D-I in FRTL-5 cells is probably mediated through post-thyrotropin-induced generation of cyclic adenosine monophosphate (cAMP) because TNF-α inhibited both dibutyryl cAMP (p < 0.001) and forskolin (p < 0.001)-induced increases in 5′D-I without affecting cAMP generation stimulated by thyrotropin. In conclusion, we have demonstrated that TNF-α inhibits thyrotropininduced 5′D-I activity in FRTL-5 cells by pathways distal to the generation of cAMP and that TNF-α may play a role in the modulation of the production of triiodothyronine by the thyroid gland. Furthermore, the increase in TNF-α observed in patients with the euthyroid sick syndrome may contribute to the low serum triiodothyronine observed in these patients, not only by inhibiting peripheral generation of triiodothyronine from thyroxine but also by decreasing thyroidal generation and subsequent secretion of triiodothyronine.
Lewis E Braverman, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA
Purification and biologic characterization of a specific tumor necrosis factor α inhibitor