Methimazole inhibits CXC chemokine ligand 10 secretion in human thyrocytes
Methimazole inhibits CXC chemokine ligand 10 secretion in human thyrocytes
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DOI：
10.1677/joe-07-0240
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发表时间：
2007-10-01
影响因子：
4
通讯作者：
Serio, M.
中科院分区：
文献类型：
--
作者：
Crescioli, C.;Cosmi, L.;Serio, M.
CXC趋化因子配体10（CXCL 10）在自身免疫性甲状腺疾病患者的炎症过程中发挥关键作用。甲巯咪唑（MMI）治疗可降低Graves病患者的血清CXCL 10水平。在分离的人甲状腺细胞中，肿瘤坏死因子（TNF）α对干扰素（IFN）γ诱导的CXCL 10分泌具有强效协同作用。我们研究了IFN γ和TNF α之间协同作用的机制以及MMI对人甲状腺细胞CXCL 10分泌的影响。一种过氧化物酶体增殖物激活受体γ激动剂，罗格列酮（RGZ），一种已知的辅助性T细胞1（Th 1）介导的反应的抑制剂，也进行了比较研究。本实验从多结节性甲状腺肿手术切除的甲状腺组织中分离甲状腺细胞。ELISA用于测量培养上清液中的CXCL 10水平。流式细胞术用于评估IFN γ膜受体表达。通过Taqman实时PCR进行特异性mRNA分析。免疫荧光法检测核因子-κ B（NF-κ B）的核转位。在人甲状腺细胞中，TNF α与IFN γ对CXCL 10分泌的协同作用是由于IFN γ受体表达的上调。MMI通过减少TNF α诱导的IFN γ受体上调来降低马槟榔诱导的CXCL 10分泌。RGZ通过损害NF-κ B B易位而降低了IFN γ诱导的CXCL 10分泌，而不影响IFN γ受体。MMI和RGZ以相同的药理学效力靶向甲状腺细胞，可能通过不同的机制起作用。靶向T辅助细胞I介导的自身免疫性甲状腺疾病的药物，损害不同的细胞内途径可能是一种新的药理学工具。
CXC chemokine ligand 10 (CXCL10) plays a pivotal role in the self perpetuation of the inflammatory processes in patients with autoimmune thyroid disease. Treatment with methimazole (MMI) reduces serum CXCL10 in patients with Graves' disease. In isolated human thyrocytes, tumor necrosis factor (TNF)alpha demonstrates a potent synergistic effect on interferon (IFN)gamma-induced CXCL10 secretion. We investigated the mechanism underlying the synergism between IFN gamma and TNF alpha and the effect of MMI on CXCL10 secretion in human thyrocytes. A peroxisome proliferator-activated receptor gamma agonist, rosiglitazone (RGZ), a known inhibitor of T helper 1 (Th1)-mediated responses, was also studied for comparison. Experiments were carried out in human thyrocytes isolated from internodular parenchyma of thyroid tissues derived front patients who had undergone surgery for multinodular goiter. ELISA was used to measure CXCL10 levels in culture supernatant. Flow cytometry was used to assess IFN gamma membrane receptor expression. Specific mRNA analysis was performed by Taqman real-time PCR. Immunofluorescence was performed to detect nuclear translocation of nuclear factor-kappa B (NF-kappa B). In human thyrocytes, the synergistic effect of TNF alpha with IFN gamma on CXCL10 secretion is due to the upregulation of IFN gamma receptor expression. MMI decreased cytokine-induced CXCL10 secretion by reducing TNF alpha-induced upregulation of the IFN gamma receptor. RGZ decreased the cytokine-induced CXCL10 secretion by impairing NF-kappa B translocation, without affecting IFN gamma receptor. MMI and RGZ targeted thyrocytes with the same pharmacological potency, likely acting throughout different mechanisms. Targeting T helper I-mediated autoimmune thyroid disease with drugs that impair different intracellular pathways could be a novel pharmacological tool.