Bim deficiency leads to exacerbation and prolongation of joint inflammation in experimental arthritis
Bim deficiency leads to exacerbation and prolongation of joint inflammation in experimental arthritis
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DOI：
10.1002/art.22133
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发表时间：
2006-10-01
影响因子：
--
通讯作者：
Perlman, Harris
中科院分区：
文献类型：
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作者：
Scatizzi, John C.;Bickel, Emily;Perlman, Harris
目的：类风湿性关节炎（RA）是一种以滑膜增生、炎症、软骨和骨破坏为特征的疾病。由于关节中只有少数可检测到的细胞发生凋亡，因此凋亡缺陷可能导致滑膜增生。本研究旨在确定和表征细胞凋亡调节因子在小鼠炎症性关节炎模型中的直接作用。使用血清转移模型，实验性关节炎。与野生型（WT）对照小鼠相比，在缺乏促细胞凋亡Bcl-2家族基因巴克（巴克（-/-））、Bax（Bax（-/-））或Bim（Bim（-/-））的小鼠中诱导。踝关节水肿的物理检查和踝关节切片的组织病理学分析用于确定关节炎的严重程度。采用酶联免疫吸附法或Luminex法检测血清和踝关节趋化因子和细胞因子的产生。Bim（-/-）小鼠表现出关节炎的严重程度增加和延长。相反，与WT小鼠相比，巴克（-/-）和Bax（-/-）小鼠在关节炎的严重程度上没有显示出差异。此外，与WT小鼠相比，Bim（-/-）小鼠的促炎趋化因子和细胞因子水平升高，关节和血清中抗炎细胞因子的产生减少，TUNEL阳性细胞减少，活性半胱天冬酶3水平降低。结论。这些研究是第一次证明了促凋亡Bcl-2蛋白Bim在RA效应期的作用。研究结果表明，Bim可能通过调节关节和血清的环境以及诱导细胞凋亡来抑制关节炎的效应期。
Objective: Rheumatoid arthritis (RA) is characterized by hyperplasia of the synovial lining, inflammation, and destruction of cartilage and bone. Since there are only a few detectable cells undergoing apoptosis in the joint, it is possible that a defect in apoptosis may contribute to synovial hyperplasia. This study sought to identify and characterize the direct role of apoptotic regulators in a mouse model of inflammatory arthritis.Methods. Using a serum transfer model, experimental arthritis was. induced in mice lacking the proapoptotic Bcl-2 family genes Bak (Bak(-/-)), Bax (Bax(-/-)), or Bim (Bim(-/-)), as compared with wild-type (WT) control mice. Physical examination for edema of the ankles and histopathologic analysis of ankle sections were used to determine the severity of arthritis. The serum and ankles were examined for production of chemokines and cytokines using enzyme-linked immunosorbent or Luminex-based assays.Results. Bim(-/-) mice displayed increased severity and prolongation of arthritis. In contrast, Bak(-/-) and Bax(-/-) mice showed no difference in the severity of arthritis as compared with WT mice. In addition, Bim(-/-) mice had elevated levels of proinflammatory chemokines and cytokines, decreased joint and serum production of antiinflammatory cytokines, fewer TUNEL-positive cells, and reduced levels of active caspase 3 as compared with WT mice.Conclusion. These studies are the first to demonstrate a role for the proapoptotic Bcl-2 protein Bim in the effector phase of RA. The findings indicate that Bim potentially functions to repress the effector phase of arthritis by regulating the milieu of the joint and serum, and by inducing apoptosis.