IL-6 promotes nonthyroidal illness syndrome by blocking thyroxine activation while promoting thyroid hormone inactivation in human cells

Nonthyroidal illness syndrome (NTIS) is a state of low serum 3,5,3' triiodothyronine (T-3) that occurs in chronically ill patients; the degree of reduction in T3 is associated with overall prognosis and survival. Iodothyronine deiodinases are enzymes that catalyze iodine removal from thyroid hormones; type I and II deiodinase (D1 and D2, respectively) convert the prohormone thyroxine T-4 to active T-3, whereas the type III enzyme (D3) inactivates T-4 and T-3. Increased production of cytokines, including IL-6, is a hallmark of the acute phase of NTTS, 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 deioclinase activities in human cell lines. Active T-3 generation by D1 and D2 in intact cells was suppressed by IL-6, despite an increase in sonicate deioclinases (and mRNAs). N-acetylcysteine (NAC), an antioxidant that restores intracellular glutathione (GSH) concentrations, prevented the IL-6-induced inhibitory effect on D1- and D2-mediated T-3 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 T-3. Taken together, these results identify a single pathway by which IL-6-induced oxidative stress can reduce D1- and D2-mediated T-4-to-T-3 conversion as well as increasing D3-mediated T-3 (and T-4) inactivation, thus mimicking events during illness.