Overexpression of Bcl-2 in transgenic mice decreases apoptosis and improves survival in sepsis.
Overexpression of Bcl-2 in transgenic mice decreases apoptosis and improves survival in sepsis.
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DOI：
10.4049/jimmunol.162.7.4148
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发表时间：
1999-04
影响因子：
4.4
通讯作者：
R. Hotchkiss;P. Swanson;C. Knudson;Katherine C. Chang;J. Cobb;D. Osborne;K. Zollner;T. Buchman;S. Korsmeyer;I. Karl
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文献类型：
--
作者：
R. Hotchkiss;P. Swanson;C. Knudson;Katherine C. Chang;J. Cobb;D. Osborne;K. Zollner;T. Buchman;S. Korsmeyer;I. Karl
在脓毒症中，淋巴细胞存在广泛的凋亡，这可能通过下调伴随的炎症而受益。或者，通过损害宿主防御，细胞凋亡可能是有害的。在一个临床相关的脓毒症模型中，我们研究了一种有效的抗细胞凋亡蛋白Bcl2是否可以阻止淋巴细胞的凋亡。在T细胞中高表达Bcl2的转基因小鼠对脓毒症诱导的胸腺和脾T细胞凋亡具有完全的保护作用。令人惊讶的是，与脓毒症HeJ和HeOuJ小鼠相比，脓毒症Bcl2过表达的小鼠脾B细胞凋亡也减少。3种脓毒症小鼠胸腺组织中TNF-α、IL-1β和IL-10均显著升高，其中HeOuJ小鼠的升高幅度大于Bcl2小鼠。线粒体膜电位指示剂Mitotracker显示，脓毒症导致HeJ和HeOuJ小鼠T细胞膜电位丧失，但在Bcl2小鼠中未见。重要的是，Bcl-2过表达基因也改善了脓毒症患者的存活率。为了研究淋巴细胞丢失对脓毒症患者存活的潜在影响，还研究了成熟T和B细胞完全缺乏的RAG-1-/-小鼠。与免疫正常的脓毒症小鼠相比，RAG-1-/-小鼠的存活率降低。我们的结论是，在脓毒症中，过表达的Bcl2对细胞死亡具有保护作用。淋巴细胞死亡在脓毒症中可能是有害的，因为它损害了宿主的防御。
In sepsis there is extensive apoptosis of lymphocytes, which may be beneficial by down-regulating the accompanying inflammation. Alternatively, apoptosis may be detrimental by impairing host defense. We studied whether Bcl-2, a potent antiapoptotic protein, could prevent lymphocyte apoptosis in a clinically relevant model of sepsis. Transgenic mice in which Bcl-2 was overexpressed in T cells had complete protection against sepsis-induced T lymphocyte apoptosis in thymus and spleen. Surprisingly, there was also a decrease in splenic B cell apoptosis in septic Bcl-2 overexpressors compared with septic HeJ and HeOuJ mice. There were marked increases in TNF-alpha, IL-1beta, and IL-10 in thymic tissue in sepsis in the three species of mice, and the increase in TNF-alpha and IL-10 in HeOuJ mice was greater than that in Bcl-2 mice. Mitotracker, a mitochondrial membrane potential indicator, demonstrated a sepsis-induced loss of membrane potential in T cells in HeJ and HeOuJ mice but not in Bcl-2 mice. Importantly, Bcl-2 overexpressors also had improved survival in sepsis. To investigate the potential impact of loss of lymphocytes on survival in sepsis, Rag-1-/- mice, which are totally deficient in mature T and B cells, were also studied. Rag-1-/- mice had decreased survival compared with immunologically normal mice with sepsis. We conclude that overexpression of Bcl-2 provides protection against cell death in sepsis. Lymphocyte death may be detrimental in sepsis by compromising host defense.