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

J Clin Invest. 2011 May;121(5):1834-45. doi: 10.1172/JCI44678. Epub 2011 Apr 11.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / chemistry
  • Cell Line
  • Cell Line, Tumor
  • Cytokines / metabolism
  • Dithiothreitol / pharmacology
  • Glutathione / metabolism
  • Humans
  • Interleukin-6 / metabolism*
  • Oxidative Stress
  • RNA, Messenger / metabolism
  • Reactive Oxygen Species
  • Thyroid Diseases / metabolism*
  • Thyroid Hormones / metabolism*
  • Thyroxine / metabolism*


  • Cytokines
  • Interleukin-6
  • RNA, Messenger
  • Reactive Oxygen Species
  • Thyroid Hormones
  • Glutathione
  • Thyroxine
  • Dithiothreitol
  • Acetylcysteine