title: IL-6 promotes nonthyroidal illness syndrome by blocking thyroxine activation while promoting thyroid hormone inactivation in human cells.
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.
authors.affiliation: Thyroid Section, Endocrine Division, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Simone Magagnin
authors.initials: SM
authors.lastname: Wajner
authors.forename: Iuri Martin
authors.initials: IM
authors.lastname: Goemann
authors.forename: Ana Laura
authors.initials: AL
authors.lastname: Bueno
authors.forename: P Reed
authors.initials: PR
authors.lastname: Larsen
authors.forename: Ana Luiza
authors.initials: AL
authors.lastname: Maia
mesh_terms: D000111:Acetylcysteine / Q000737:chemistry; D002460:Cell Line; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D004229:Dithiothreitol / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species; D013959:Thyroid Diseases / Q000378:metabolism*; D013963:Thyroid Hormones / Q000378:metabolism*; D013974:Thyroxine / Q000378:metabolism*
chemical_list: D016207:Cytokines; D015850:Interleukin-6; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D013963:Thyroid Hormones; D005978:Glutathione; D013974:Thyroxine; D004229:Dithiothreitol; D000111:Acetylcysteine