Iodine Overdose Promotes Pathogenesis Of Hashimoto’s Thyroiditis Via Induction Of Th17Cells

Objectives:Hashimoto’s thyroiditis (HT) is the most common thyroid disease that cause hypothyroidism in clinical practise, yet its pathogenesis and its associated molecular mechanisms remain unclear. Various epidemiological evidence has demonstrated that:the incidence of HT is associated with the overdose of iodine intake. However, how iodine overdose causes the pathogenesis of HT and its underlying molecular mechanism are rarely studied. In addition, the effect of iodine on immune system is yet to be unfolded. This study analyzed the IL-17expression in patients with HT, and then explored the role of iodine in the pathogenesis of HT and its effect on immune system.Materials and Methods:Tissue infiltrated lymphocytes were determined by flowcytometry in HT patients and control subjects.169patients (including82HT patients with HT,53patients with nodular goiter,34patients with thyroid cancer) and60healthy controls were recruited from July,2009to September,2011. ELISA was used to determine the levels of serum IL-17, TGF-β1, IL-6and IL-1β.Patients with HT were grouped according to their oral thyroxin intake (transient hyperthyroidism,0～25μg,25～75μg and over87.5μg) for the evaluation of IL-17expression. The correlation of IL-17expression and thyroid pathology was studied.To further determine the pathogenesis of HT, we established murine autoimmune thyroiditis model via high iodine diet followed by murine Tg immunization. C57mice were fed with different amounts of drinking iodine and challenged with murine Tg. Splenic expression of IL-17and IFN-y was determined using conventional, real-time PCR and flowcytometry; the frequency of splenic Treg was determined by flowcytometry.Results The frequency of thyroid CD3+IL-17+Th17cells was significantly increased in thyroid gland from HT patients, compared with that of controls; and the levels of serum IL-17, IL-6, IL-1β was higher that than in controls; IL-17levels decreased with respect to oral thyroxin intake. In vivo study in mice autoimmune thyroiditis model showed that moderate high level of feeding iodine(1500μg/L) facilitates the polarization of splenic naive T cells into Thl7cells, while in extreme high level condition(24000μg/L), iodine redirects T cell differentiation into Thl polarization. Meanwhile, iodine inhibits the frequency of splenic CD3+Foxp3+regulatory T cells in a dose dependent manner.Conclusions:IL-17may play a role in the early stage of HT, and may correlate with thyroid local fibrosis. High iodine level may selectively promote the polarization of Thl and Th17cells while inhibit the development of Tregs, thus promoting the pathogenesis of HT. Objectives:A role of inflammation in tumorigenesis is now widely accepted, and it has become evident that a chronic inflammatory microenvironment is an essential component of tumors. However, the mechanism of which yet remained unclear. Toll-like receptors are recently identified receptor family expressed on immune cells as well as tumor cells, initiating and promoting the pathogenesis of tumor. Tumor cells expressing TLRs is generally recognized to mediate tumor inflammation. However, whether and how tumor TLR signaling pathways negatively regulate tumor inflammation remains unclear. Furthermore, tumor cells, when being stimulated or apototic, releases membrane bounded microparticles to regulate tumor inflammation. In this study, we investigated the downstream signaling and the biological effects of TLR on H22cells and more importantly, its potential negative regulation of tumor inflammation.Materials and methods:We first investigated the effect of LPS on the release of MP as well as its underlying mechanism, then miRNA expression pattern in microparticle was analyzed the by miRNA array. We determined the effect of LPS induced microparticle on macrophages, and demonstrated the regulating mechanism through which miRNA was transferred from tumor cells to macrophages.Results:LPS induced the released of microparticles of H22tumor cells. We find that this TLR4signaling is transduced through MyD88pathway to actin cytoskeletons, leading to the release of microparticles. MiRNA array analysis showed that the expression of miRNA-let-7b was abundant in tumor released micropartiles. As a result, macrophages take up MPs and acquire MP-contained microRNA let-7b, which attenuates tumor inflammation by targeting proinflammatory cytokine IL-6. Conclusions:Tumor TLR signaling, contrary to the original promoting effect, may play an opposite role in downregulating tumor inflammation through MP pathways.