Schering-Plough Research Institute, PO box 20, 5340 BH Oss, The Netherlands.
Arthritis Res Ther. 2010;12(3):R101. doi: 10.1186/ar3032. Epub 2010 May 24.
The immune modulatory role of estrogens in inflammation is complex. Both pro- and anti-inflammatory effects of estrogens have been described. Estrogens bind both estrogen receptor (ER)alpha and beta. The contribution of ERalpha and ERbeta to ER-mediated immune modulation was studied in delayed type hypersensitivity (DTH) and in experimental arthritis
ER-mediated suppression of rat adjuvant arthritis (AA) was studied using ethinyl-estradiol (EE) and a selective ERbeta agonist (ERB-79). Arthritis was followed for 2 weeks. Next, effects of ER agonists (ethinyl-estradiol, an ERalpha selective agonist (ERA-63) and a selective ERbeta agonist (ERB-79) on the development of a tetanus toxoid (TT)-specific delayed type hypersensitivity response in wild type (WT) and in ERalpha- or ERbeta-deficient mice were investigated. Finally, EE and ERA-63 were tested for their immune modulating potential in established collagen induced arthritis in DBA/1J mice. Arthritis was followed for three weeks. Joint pathology was examined by histology and radiology. Local synovial cytokine production was analyzed using Luminex technology. Sera were assessed for COMP as a biomarker of cartilage destruction.
EE was found to suppress clinical signs and symptoms in rat AA. The selective ERbeta agonist ERB-79 had no effect on arthritis symptoms in this model. In the TT-specific DTH model, EE and the selective ERalpha agonist ERA-63 suppressed the TT-specific swelling response in WT and ERbetaKO mice but not in ERalphaKO mice. As seen in the AA model, the selective ERbeta agonist ERB-79 did not suppress inflammation. Treatment with EE or ERA-63 suppressed clinical signs in collagen induced arthritis (CIA) in WT mice. This was associated with reduced inflammatory infiltrates and decreased levels of proinflammatory cytokines in CIA joints.
ERalpha, but not ERbeta, is key in ER-mediated suppression of experimental arthritis. It remains to be investigated how these findings translate to human autoimmune disease.
雌激素在炎症中的免疫调节作用很复杂。已经描述了雌激素的促炎和抗炎作用。雌激素结合雌激素受体（ER）alpha 和 beta。本研究旨在研究 ER 介导的免疫调节中 ERalpha 和 ERbeta 的作用，研究对象为迟发型超敏反应（DTH）和实验性关节炎。
使用乙炔雌二醇（EE）和选择性 ERbeta 激动剂（ERB-79）研究 ER 介导的大鼠佐剂性关节炎（AA）的抑制作用。关节炎持续 2 周。接下来，研究 ER 激动剂（乙炔雌二醇、ERalpha 选择性激动剂（ERA-63）和选择性 ERbeta 激动剂（ERB-79）对野生型（WT）和 ERalpha 或 ERbeta 缺陷型小鼠破伤风类毒素（TT）特异性迟发型超敏反应发展的影响。最后，在 DBA/1J 小鼠建立的胶原诱导性关节炎中测试 EE 和 ERA-63 的免疫调节作用。关节炎持续 3 周。通过组织学和放射学检查评估关节病理。使用 Luminex 技术分析局部滑膜细胞因子的产生。评估血清 COMP 作为软骨破坏的生物标志物。
发现 EE 可抑制大鼠 AA 的临床症状和体征。选择性 ERbeta 激动剂 ERB-79 对该模型的关节炎症状无影响。在 TT 特异性 DTH 模型中，EE 和选择性 ERalpha 激动剂 ERA-63 抑制 WT 和 ERbetaKO 小鼠的 TT 特异性肿胀反应，但对 ERalphaKO 小鼠无影响。与 AA 模型一样，选择性 ERbeta 激动剂 ERB-79 并未抑制炎症。EE 或 ERA-63 治疗可抑制 WT 小鼠胶原诱导性关节炎（CIA）的临床症状。这与 CIA 关节中炎症浸润减少和促炎细胞因子水平降低有关。
ERalpha，而不是 ERbeta，是 ER 介导的实验性关节炎抑制的关键。这些发现如何转化为人类自身免疫性疾病还有待研究。
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