Increased Interleukin-23 in Hashimoto’s Thyroiditis Disease Induces Autophagy Suppression and Reactive Oxygen Species Accumulation

Abstract

Hashimoto’s thyroiditis (HT) represents the most common organ-specific autoimmune disease. Inflammatory factors and reactive oxygen species (ROS) play detrimental roles during the pathogenesis of HT. In this study, we found that thyroid follicular cells (TFCs) from HT patients expressed an elevated level of interleukin-23 (IL-23), which contributed to autophagy suppression and ROS accumulation. Additionally, IL-23-induced autophagy suppression and ROS accumulation in human TFCs was attributed to AKT/mTOR/NF-κB signaling pathway activation. Inhibition of either IL-23 by a specific neutralization antibody, or mTOR by rapamycin, or NF-κB by IKK-16, significantly reversed the autophagy suppression and ROS accumulation. These results demonstrate a key role for IL-23 in HT pathogenesis and provide a potential therapeutic strategy against IL-23 or its signaling pathway in HT.

Caveolin-1 regulates autophagy activity in thyroid follicular cells and is involved in Hashimoto’s thyroiditis disease

“…Increasing evidence indicates the importance of autophagy in the pathogenesis and development of inflammation [58,59]. Previous work from our laboratory has found that the LC3B-II protein expression in TFC was sharply decreased in HT tissues compared with that of the healthy controls [23,24]. In this study, LC3B-II expression in TFC was significantly decreased following treatment with IL-1β and IFN-γ, suggesting that autophagy activity in TFC was suppressed under a Th1 cytokines environment.…”

“…Inhibition of autophagy may contribute to a bioenergetic shortage and favour oxidative reactions that trigger cell death characterized by hallmarks of apoptosis [22]. Autophagy activity is decreased and apoptosis level is increased in HT thyroids compared to in control thyroids [23,24]. Cav-1 has been associated with the apoptosis of thyroid cells [18].…”

Upregulated tissue expression of T helper (Th) 17 pathogenic interleukin (IL)-23 and IL-1β in Hashimoto’s thyroiditis but not in Graves’ disease

“…Therefore, these results as well as conclusions regarding the role of Th17 cells in GD pathogenesis must be interpreted with caution because the absolute number of patients with GD was only 8. Interestingly, Zheng et al showed an increase in IL-17 and RORγt mRNA expression in IL-23-stimulated cultured cells from GD patients when compared to those from controls and cultures without IL-23 [14]. Similar results were demonstrated in euthyroid GD patients, indicating an independent effect of thyroid hormone levels [29].…”

“…IL-37 exerts a protective role against oxidative stress and inflammation by inhibiting effects of Th1/Th17-mediated response [27]. Recently, another research group found the enhanced expression of IL-23 in the thyroid tissue of patients with HT when compared to controls [14]. Additionally, these authors demonstrated the accumulation of reactive oxygen species and the inhibition of autophagy in thyrocytes induced by increased IL-23.…”

“…Interestingly, although IL-23 is not required for the induction of Th17 differentiation (naïve T cells do not express IL-23 receptor), IL-23-dependent signaling is crucial for the generation of highly pathogenic Th17 cells via signal transducer and activator of transcription (STAT) 4 [12]. It has recently been reported that IL-23 levels are enhanced in the peripheral blood [13] and thyroid tissues [14] of HT patients; however, it is still unknown whether IL-23 is involved in the pathogenesis of GD. IL-1β is another pro-inflammatory cytokine that participates in AITD [15] and is essential for the conversion of classical Th17 lymphocytes into the pathogenic Th17 subset [16].…”