A role for the aryl hydrocarbon receptor and the dioxin TCDD in rheumatoid arthritis
A role for the aryl hydrocarbon receptor and the dioxin TCDD in rheumatoid arthritis
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DOI：
10.1093/rheumatology/ken259
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发表时间：
2008-09-01
期刊：
影响因子：
5.5
通讯作者：
Momohara, S.
中科院分区：
文献类型：
--
作者：
Kobayashi, S.;Okamoto, H.;Momohara, S.
客观的。环境因素参与RA发病机制，流行病学研究表明吸烟是RA的环境危险因素。 2,3,7,8-四氯二苯并-对二恶英（TCDD）是卷烟中的主要有毒成分之一。为了阐明吸烟对 RA 的生物学影响，我们研究了 TCDD 在 RA 发病机制中的作用。方法。从 RA 和 OA 患者获得人类滑膜组织，并使用免疫组织化学和实时 PCR 评估这些组织中芳基烃受体 (AhR) 的表达。用不同浓度的 TCDD 刺激 RA 滑膜细胞后，通过实时 PCR 测量各种细胞因子的表达。为了研究 AhR 的作用，我们用 α-萘黄酮（一种已知的 AhR 拮抗剂）处理 RA 滑膜细胞。为了评估哪些信号转导途径受到 TCDDAhR 相互作用的刺激，我们使用了核因子 kappa B (NF-kappa B) 和细胞外刺激激活激酶 (ERK) 的抑制剂。结果。在 RA 滑膜组织中观察到的 AhR mRNA 和蛋白质水平高于 OA 组织。 TCDD 通过与 AhR 结合上调 IL-1 beta、IL-6 和 IL-8 的表达，并且这种效应通过 NF-κ B 和 ERK 信号级联传递。 TNF-α上调滑膜细胞中AhR的表达。结论。 TNF-α 激活 RA 滑膜组织中的 AhR 表达，吸烟和接触 TCDD 会增强 RA 炎症过程。 TCDD 通过与 AhR 结合诱导炎症细胞因子，从而刺激 NF-kappa B 和 ERK 信号级联。因此，TCDD 暴露（例如吸烟）会加剧 RA 的病理生理学。
Objective. Environmental factors are involved in RA pathogenesis and epidemiological studies have suggested that smoking is an environmental risk factor for RA. The 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is one of the major toxic components in cigarettes. To clarify the biological effects of smoking in RA, we investigated the role of TCDD in RA pathogenesis.Methods. Human synovial tissue was obtained from RA and OA patients and aryl hydrocarbon receptor (AhR) expression in these tissues was evaluated using immunohistochemistry and real-time PCR. Expression of various cytokines was measured by real-time PCR following stimulation of RA synoviocytes with different concentrations of TCDD. To study the role of AhR, we treated RA synoviocytes with alpha-naphthoflavone, a known AhR antagonist. To evaluate which signal transduction pathways were stimulated by the TCDDAhR interaction, we used inhibitors of nuclear factor-kappa B (NF-kappa B) and extra-cellular stimulus-activated kinase (ERK).Results. Higher AhR mRNA and protein levels were observed in RA synovial tissue than in OA tissue. TCDD up-regulated the expression of IL-1 beta, IL-6 and IL-8 through binding to AhR, and this effect was transmitted via the NF-kappa B and ERK signalling cascades. AhR expression in synovial cells was up-regulated by TNF-alpha.Conclusion. TNF-alpha activates AhR expression in RA synovial tissue, and that cigarette smoking and exposure to TCDD enhances RA inflammatory processes. TCDD induces inflammatory cytokines via its association with AhR, resulting in stimulation of the NF-kappa B and ERK signalling cascades. Thus TCDD exposure, such as smoking exacerbates RA pathophysiology.