Modulation of adjuvant arthritis in the rat by 2-methoxyestradiol: An effect independent of an anti-angiogenic action
Modulation of adjuvant arthritis in the rat by 2-methoxyestradiol: An effect independent of an anti-angiogenic action
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DOI：
10.1016/j.intimp.2008.01.016
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发表时间：
2008-05-01
影响因子：
5.6
通讯作者：
Sapru, Kusum
中科院分区：
文献类型：
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作者：
Issekutz, Andrew C.;Sapru, Kusum
血管生成是类风湿性关节炎的一个突出特征。 2-methoxyestradiol (2ME2) 抑制体内内皮细胞增殖和血管生成。我们评估了 2ME2 对患有佐剂性关节炎 (AA) 的大鼠的作用，佐剂性关节炎是一种由分枝杆菌免疫诱导的自身免疫性 T 细胞依赖性多关节关节炎。用丁酸分枝杆菌对大鼠进行免疫，并通过放射性标记的血液中性粒细胞（PMNL）迁移至关节并通过组织学对关节炎进行临床评估。从免疫后第6天开始用2ME2（30 mg/kg/d或100 mg/kg/d）治疗可抑制第14天的关节炎严重程度（车辆临床评分=11.2；2ME2组=7-8，p < 0.05）。当延迟治疗直至免疫后第 10 天出现临床关节炎症状时，2ME2 治疗仍能抑制关节炎的严重程度。早期 2ME2 治疗（第 6-14 天）显着抑制 PMNL 向关节的迁移（抑制 35-40%；p < 0.01）。 2ME2 治疗可抑制 PMNL 迁移至 TNF-α 诱导的真皮炎症，但不能抑制 LPS 或 CSa 诱导的炎症。关节组织学显示白细胞浸润减少，尤其是软骨损伤减少。然而，滑膜血管分布并未受到 2ME2 治疗的影响。 2ME2 治疗可预防与 AA 相关的显着脾肿大、脾炎和淋巴组织增生。此外，2ME2 AA 治疗大鼠的淋巴细胞对分枝杆菌抗原 (PPD) 的离体增殖反应显着减弱，但对丝裂原的反应不受影响。因此，2ME2 具有抗关节炎特性和疾病缓解作用，与其抗血管生成特性不同。选择性抑制 TNF-α 诱导的白细胞募集、淋巴增生和对抗原的记忆反应减弱表明 2ME2 具有免疫调节和抗炎作用。 (c) 2008 Elsevier B.V. 保留所有权利。
Angiogenesis is a prominent feature in rheumatoid arthritis. 2-methoxyestradiol (2ME2) inhibits endothelial cell proliferation, and angiogenesis in vivo. We evaluated the effect of 2ME2 in rats with adjuvant arthritis (AA), an autoimmune T-cell-dependent polyarticular arthritis induced by immunization with Mycobacterium organisms. Rats were immunized with Mycobacterium butyricum and arthritis was assessed clinically, by radiolabeled blood neutrophil (PMNL) migration to joints and by histology. Treatment with 2ME2 (30 mg/kg/d or 100 mg/kg/d) from day 6 post-immunization inhibited arthritis severity on day 14 (vehicle clinical score=11.2; 2ME2 groups=7-8, p < 0.05). When treatment was delayed until signs of clinical arthritis on day 10 post-immunization, 2ME2 treatment still inhibited arthritis severity. PMNL migration to the joints was significantly inhibited (by 35-40%; p < 0.01) by early 2ME2 treatment (day 6-14). Treatment with 2ME2 inhibited PMNL migration to dermal inflammation induced by TNF-alpha but not by LPS or CSa. Joint histology revealed decrease in leukocyte infiltration and especially in cartilage damage. However, synovial vascularity was not affected by 2ME2 treatment. The marked splenomegaly, splenitis and lymphoid hyperplasia associated with AA were prevented by 2ME2 therapy. Furthermore, the ex vivo proliferative response to mycobacterial antigen (PPD) of lymphocytes from 2ME2-treated rats with AA was markedly diminished, although response to mitogens was unaffected. Thus 2ME2 has anti-arthritic properties with a disease-modifying action, separate from its anti-angiogenic properties. The selective inhibition of TNF-alpha-induced leukocyte recruitment, lymphoid hyperplasia and attenuated recall response to antigen suggests both immunomodulatory and anti-inflammatory actions of 2ME2. (c) 2008 Elsevier B.V. All rights reserved.