Yepes Manuel, Brown Sharron A N, Moore Elizabeth G, Smith Elizabeth P, Lawrence Daniel A, Winkles Jeffrey A
Department of Surgery, University of Maryland School of Medicine, 15601 Crabbs Branch Way, Rockville, MD 20855, USA.
Am J Pathol. 2005 Feb;166(2):511-20. doi: 10.1016/S0002-9440(10)62273-0.
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumor necrosis factor superfamily. TWEAK acts on responsive cells via binding to a small cell surface receptor named Fn14. Recent studies have demonstrated that TWEAK can stimulate numerous cellular responses including cell proliferation, migration, and proinflammatory molecule production, but the role of this cytokine in cardiovascular disease and stroke has not been established. The present study investigated whether TWEAK or Fn14 expression was regulated in a murine model of cerebral ischemia and whether TWEAK played a role in ischemia-mediated cell death. We found that TWEAK and Fn14 were expressed by primary mouse cerebral cortex-derived astrocytes and neurons cultured in vitro. Also, both the TWEAK and Fn14 proteins were present at elevated levels in the ischemic penumbra region after middle cerebral artery occlusion. Finally, we report that intracerebroventricular injection of a soluble Fn14-Fc decoy receptor immediately after middle cerebral artery occlusion significantly reduced infarct volume and the extent of microglial cell activation and apoptotic cell death in the ischemic penumbra. We conclude that the cytokine TWEAK may play an important role in ischemia-induced brain injury and that inhibition of TWEAK expression or function in the brain may represent a novel neuroprotective strategy to treat ischemic stroke.
肿瘤坏死因子样凋亡微弱诱导剂(TWEAK)是肿瘤坏死因子超家族的一员。TWEAK通过与一种名为Fn14的小细胞表面受体结合作用于反应性细胞。最近的研究表明,TWEAK可刺激多种细胞反应,包括细胞增殖、迁移和促炎分子产生,但这种细胞因子在心血管疾病和中风中的作用尚未明确。本研究调查了在小鼠脑缺血模型中TWEAK或Fn14的表达是否受到调节,以及TWEAK在缺血介导的细胞死亡中是否发挥作用。我们发现,原代小鼠大脑皮层来源的星形胶质细胞和体外培养的神经元表达TWEAK和Fn14。此外,大脑中动脉闭塞后,缺血半暗带区域的TWEAK和Fn14蛋白水平均升高。最后,我们报告,大脑中动脉闭塞后立即脑室内注射可溶性Fn14-Fc诱饵受体可显著减小梗死体积,并减轻缺血半暗带区域小胶质细胞激活和凋亡细胞死亡的程度。我们得出结论,细胞因子TWEAK可能在缺血性脑损伤中起重要作用,抑制大脑中TWEAK的表达或功能可能代表一种治疗缺血性中风的新型神经保护策略。