IL-6 promotes nonthyroidal illness syndrome by blocking thyroxine activation while promoting thyroid hormone inactivation in human cells
Year: 2011
Type: article
Abstract: Nonthyroidal illness syndrome (NTIS) is a state of low serum 3,5,3' triiodothyronine (T₃) that occurs in chronically ill patients; the degree of reduction in T₃ is associated with overall prognosis and survival. Iodthyronine deiodinases are enzymes that catalyze iodine removal from thyroid hormones; type I and II deiodinase (D1 and D2, respectively) convert the prohormone thyroxine T₄ to active T₃, whereas the type III enzyme (D3) inactivates T₄ and T₃. Increased production of cytokines, including IL-6, is a hallmark of the acute phase of NTIS, but the role of cytokines in altered thyroid hormone metabolism is poorly understood. Here, we measured the effect of IL-6 on both endogenous cofactor-mediated and dithiothreitol-stimulated (DTT-stimulated) cell sonicate deiodinase activities in human cell lines. Active T₃ generation by D1 and D2 in intact cells was suppressed by IL-6, despite an increase in sonicate deiodinases (and mRNAs). N-acetyl-cysteine (NAC), an antioxidant that restores intracellular glutathione (GSH) concentrations, prevented the IL-6-induced inhibitory effect on D1- and D2-mediated T₃ production, which suggests that IL-6 might function by depleting an intracellular thiol cofactor, perhaps GSH. In contrast, IL-6 stimulated endogenous D3-mediated inactivation of T₃. Taken together, these results identify a single pathway by which IL-6-induced oxidative stress can reduce D1- and D2-mediated T₄-to-T₃ conversion as well as increasing D3-mediated T₃ (and T₄) inactivation, thus mimicking events during illness.
DOI: 10.1172/jci44678
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: Dartmouth College, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Conselho Nacional de Desenvolvimento Científico e Tecnológico, Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul, Universidade Federal do Rio Grande do Sul, Fundação Instituto de Pesquisas Econômicas, National Institutes of Health, Fogarty International Center, National Institute of Diabetes and Digestive and Kidney Diseases
OpenAlex ID: W2114397821