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 (T 3 ) that occurs in chronically ill patients; the degree of reduction in T 3 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 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 T 3 generation by D1 and D2 in intact cells was suppressed by IL-6, despite an increase in sonicate deiodinases (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.

The influence of body mass index and low-grade systemic inflammation on thyroid hormone abnormalities in patients with type 2 diabetes

“…Pro-inflammatory cytokines such as tumour necrosis factor-α [24], interleukin-1 [25] and 6 (IL-6) [26] have a major role in thyroid hormone imbalances. Serum IL-6 levels are often increased in NTIS and have been inversely correlated with T3 levels and TSH suppression [27].…”

A Low fT3 Level as a Prognostic Marker in Patients with Acute Myocardial Infarctions

“…At the same time, IL-6 can increase the transcription of D3 proteins by activating the JAK/STAT pathway. All of these changes decrease the conversion of T4 to T3 and increase the degradation of T3 (15). Hypoxia in peripheral tissues is another factor contributing to the low fT3 levels.…”

Role of thyroid hormone in skeletal muscle physiology

“…Not much is known about the mechanism involved in muscle D3 regulation during inflammation. Although D3 can be stimulated via the ERK1/2 and p38 signalling pathways in human non-muscular cells, little is known about these effects in SM (Pallud et al 1999, Wajner et al 2011.…”