碘化钾通过诱导PARP1表达活化NF-κB/NLRP3炎症小体促进甲状腺滤泡细胞焦亡

Potassium iodide promotes the pyroptosis of thyroid follicular epithelial cells through the PARP1-NF-κB-NLRP3 inflammasome activation

目的探究碘化钾诱导甲状腺滤泡细胞焦亡的分子机制。方法ELISA检测桥本甲状腺炎合并甲状腺癌组织中焦亡指标白细胞介素(interleukin,IL)-1β及IL-18的含量,以癌旁桥本甲状腺炎组织为对照;Western印迹检测焦亡标志性蛋白焦孔素(gasdermin,GSDM)的活化情况。碘化钾作用于甲状腺滤泡细胞,检测细胞焦亡IL-1β、IL-18、乳酸脱氢酶(LDH)的分泌及GSDM蛋白的活化及分子机制;转录组芯片分析高浓度碘化钾诱导甲状腺滤泡细胞差异性表达的分子及其在焦亡中的作用机制。结果桥本甲状腺炎合并甲状腺癌组织中IL-1β和IL-18细胞因子含量较同一患者癌旁桥本甲状腺炎组织显著升高(P<0.01),且焦亡标志性蛋白GSDMD的活化显著,而GSDME无显著活化改变。高浓度碘化钾作用于甲状腺滤泡细胞后,通过激活核因子-κB(NF-κB)/NLRP3信号轴诱导IL-1β、IL-18、LDH的分泌(P<0.01)和GSDMD活化,使甲状腺滤泡细胞发生焦亡。转录组芯片分析发现,甲状腺滤泡细胞受高浓度碘化钾刺激后PARP1蛋白表达显著上调,并通过调控NF-κB转录因子的活性促进细胞焦亡。结论本研究发现高浓度碘化钾通过促进PARP1蛋白表达,诱导甲状腺滤泡细胞NF-κB/NLRP3炎症小体的活化,从而诱导甲状腺滤泡细胞发生炎症性焦亡。

Objective To explore the mechanism of potassium iodide-induced pyrolysis of thyroid follicular cells.Methods Thyroid gland tissue was obtained from patients with thyroid cancer(TC)coexisting with Hashimoto′s thyroiditis,and the tumor-adjacent Hashimoto′s thyroiditis tissue was used as the control.ELISA was used to detect the concentration of the pyroptosis inflammatory cytokines interleukin(IL)-1βand IL-18 in the tissues,and Western blotting was used to detect the activation of gasdermin(GSDM)proteins,a biomarker for pyroptosis.Thyroid follicular cells treated with different concentrations of potassium iodide,and IL-1β,IL-18,lactate dehydrogenase(LDH),GSDMD were measured.Transcriptome chip analysis was used to explore the differentially expressed genes involved in pyroptosis of thyroid follicular cells induced by potassium iodide treatment.Results The levels of IL-1βand IL-18 cytokines in the tissues of patients with Hashimoto′s thyroiditis and thyroid cancer were higher than control tissues(P<0.01),and the activation of the pyroptosis executive protein GSDMD was significant increased,while GSDME was not activated.IL-1β,IL-18,and LDH secretion were significantly increased in response to potassium iodide stimulation in thyroid follicular cells(P<0.01)and GSDMD was cleaved,which indicated that potassium iodide induced the pyroptosis of thyroid follicular cells.Moreover,potassium iodide could activate NLRP3 inflammasomes to promotethe pyroptosis of thyroid follicular cells.Transcriptome chip analysis further found that PARP1 protein was highly upregulated by the stimulation of potassium iodide,and then enhanced the activity of nuclear factor-κB(NF-κB)transcription factor to induce pyroptosis.Conclusions The findings in this study reveal that potassium iodide promotesthe pyroptosis of thyroid follicular cells through activating NF-κB-NLRP3 inflammasome,which may be a novel mechanism that promots the development of Hashimoto′s thyroiditis under the condition of excessive iodine intake.PARP1 is a pivotal protein that mediates the pyroptosis induced by potassium iodide and may be a potential therapeutic target to control Hashimoto′s thyroiditis progression.