STAT6 deficiency ameliorates Graves’ disease severity by suppressing thyroid epithelial cell hyperplasia

Abstract

Signal transducer and activator of transcription 6 (STAT6) is involved in epithelial cell growth. However, little is known regarding the STAT6 phosphorylation status in Graves' disease (GD) and its role in thyroid epithelial cells (TECs). In this study, we found that STAT6 phosphorylation (p-STAT6) was significantly increased in TECs from both GD patients and experimental autoimmune Graves' disease mice and that STAT6 deficiency ameliorated GD symptoms. Autocrine IL-4 signalling in TECs activated the phosphorylation of STAT6 via IL-4 R engagement, and the downstream targets of STAT6 were Bcl-xL and cyclin D1. Thus, the IL-4-STAT6-Bcl-xL/cyclin D1 pathway is crucial for TEC hyperplasia, which aggravates GD. More importantly, in vitro and in vivo experiments demonstrated that STAT6 phosphorylation inhibited by AS1517499 decreased TEC hyperplasia, thereby reducing serum T3 and T4 and ameliorating GD. Thus, our study reveals that in addition to the traditional pathogenesis of GD, in which autoantibody TRAb stimulates thyroid-stimulating hormone receptors and consequently produces T3, T4, TRAb could also trigger TECs producing IL-4, and IL-4 then acts in an autocrine manner to activate p-STAT6 signalling and stimulate unrestricted cell growth, thus aggravating GD. These findings suggest that STAT6 inhibitors could be potent therapeutics for treating GD.

25-Hydroxyvitamin D serum level in Hashimoto’s thyroiditis, but not Graves’ disease is relatively deficient

“…Our recent observations has verified the IL-4 expression in the thyroid was significantly increased while serum IL-4 level were unaffected in EAGD mice. IL-4 derived from thyroid epithelial cells (TEC) may contribute to the pathogenesis of GD by stimulating unrestrained TEC hyperplasia [13]. Cytokines from thyroid tissue perhaps play a more critical role in the pathogenesis of GD than circulating serum cytokines.…”

“…In our very recent studies, we found IL-4 was infiltrated in the thyroid tissue of experimental autoimmune Graves' disease (EAGD) mice. IL-4 acted in an autocrine manner to activate p-STAT6 signal and stimulate unrestricted cell growth, thus aggravating GD [13]. Wang et al found direct injection of TNF-α into the thyroids of mTg-primed mice can induce thyrocyte apoptosis, indicating that pro-inflammatory TNF-α may play a critical role in thyroid destruction [14].…”

Effects of exogenous melatonin on clinical and pathological features of a human thyroglobulin-induced experimental autoimmune thyroiditis mouse model

“…Color formation was discontinued, and the intensity of the color was measured at OD 450 nm on an ELISA reader. The results of individual samples were obtained after the negative control was assigned to a value of 0.1 μg/L, and a standard curve was created 32 .…”

PEG‐Sheddable Nanodrug Remodels Tumor Microenvironment to Promote Effector T Cell Infiltration and Revise Their Exhaustion for Breast Cancer Immunotherapy

“…Signal Transducer and Activator of Transcription 6 (STAT6), the downstream signaling pathway of IL-4 and IL-13, is a key cytokine of macrophage differentiating toward M2 phenotype. [24,25] For instance, Xiao et al reported an M2 TAMs-targeted nanodrug incorporating AS and anti-IKK𝛽 siRNA. The nanodrug reversed the TME with increased CD8 + T cells and reduced Tregs via switching the polarization of M2-TAMs toward the M1 phenotype for enhanced tumor immunotherapy.…”