Division of Experimental Pathology, Institute of Pathology, University of Bern, CH-3010 Bern, Switzerland.
J Immunol. 2012 Jan 15;188(2):916-22. doi: 10.4049/jimmunol.1101864. Epub 2011 Dec 7.
The proapoptotic Bcl-2 homolog Bim was shown to control the apoptosis of both T cells and hepatocytes. This dual role of Bim might be particularly relevant for the development of viral hepatitis, in which both the sensitivity of hepatocytes to apoptosis stimuli and the persistence of cytotoxic T cells are essential factors for the outcome of the disease. The relevance of Bim in regulating survival of cytotoxic T cells or induction of hepatocyte death has only been investigated in separate systems, and their relative contributions to the pathogenesis of T cell-mediated hepatitis remain unclear. Using the highly dynamic model system of lymphocytic choriomeningitis virus-mediated hepatitis and bone marrow chimeras, we found that Bim has a dual role in the development of lymphocytic choriomeningitis virus-induced, T cell-mediated hepatitis. Although the absence of Bim in parenchymal cells led to markedly attenuated liver damage, loss of Bim in the lymphoid compartment moderately enhanced hepatitis. However, when both effects were combined in Bim(-/-) mice, the effect of Bim deficiency in the lymphoid compartment was overcompensated for by the reduced sensitivity of Bim(-/-) hepatocytes to T cell-induced apoptosis, resulting in the protection of Bim(-/-) mice from hepatitis.
促凋亡 Bcl-2 同源物 Bim 被证明可以控制 T 细胞和肝细胞的凋亡。Bim 的这种双重作用可能与病毒性肝炎的发展特别相关，在病毒性肝炎中，肝细胞对凋亡刺激的敏感性和细胞毒性 T 细胞的持续存在是疾病结局的重要因素。Bim 在调节细胞毒性 T 细胞存活或诱导肝细胞死亡中的相关性仅在单独的系统中进行了研究，其对 T 细胞介导的肝炎发病机制的相对贡献仍不清楚。使用淋巴细胞性脉络丛脑膜炎病毒介导的肝炎和骨髓嵌合体的高度动态模型系统，我们发现 Bim 在淋巴细胞性脉络丛脑膜炎病毒诱导的、T 细胞介导的肝炎的发展中具有双重作用。尽管实质细胞中缺乏 Bim 导致明显减轻的肝损伤，但淋巴样区室中 Bim 的缺失适度增强了肝炎。然而，当 Bim(-/-)小鼠中这两种作用同时发生时，Bim(-/-)肝细胞对 T 细胞诱导的凋亡的敏感性降低，Bim 在淋巴样区室中的缺失作用得到了补偿，导致 Bim(-/-)小鼠免受肝炎的影响。
