Laboratory of Systems-Oriented Immunology and Inflammation Research, Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University, Magdeburg, Germany.
Eur J Immunol. 2013 Jun;43(6):1499-510. doi: 10.1002/eji.201242819. Epub 2013 May 2.
Dysregulation of apoptosis caused by an imbalance of pro- and anti-apoptotic protein expression can lead to cancer, neurodegenerative, and autoimmune diseases. Cellular-FLIP (c-FLIP) proteins inhibit apoptosis directly at the death-inducing signaling complex of death receptors, such as CD95, and have been linked to apoptosis regulation during immune responses. While the isoforms c-FLIPL and c-FLIPS are well characterized, the function of c-FLIPR remains poorly understood. Here, we demonstrate the induction of endogenous murine c-FLIPR in activated lymphocytes for the first time. To analyze c-FLIPR function in vivo, we generated transgenic mice expressing murine c-FLIPR specifically in hematopoietic cells. As expected, lymphocytes from c-FLIPR transgenic mice were protected against CD95-induced apoptosis in vitro. In the steady state, transgenic mice had normal cell numbers and unaltered frequencies of B cells and T-cell subsets in lymphoid organs. However, when challenged with Listeria monocytogenes, c-FLIPR transgenic mice showed less liver necrosis and better bacterial clearance compared with infected wild-type mice. We conclude that c-FLIPR expression in hematopoietic cells supports an efficient immune response against bacterial infections.
细胞凋亡的失调是由于促凋亡和抗凋亡蛋白表达失衡引起的，可能导致癌症、神经退行性疾病和自身免疫性疾病。细胞-FLIP（c-FLIP）蛋白直接在死亡受体（如 CD95）的诱导信号复合物处抑制细胞凋亡，并且与免疫反应期间的细胞凋亡调节有关。虽然 c-FLIPL 和 c-FLIPS 同工型已得到很好的描述，但 c-FLIPR 的功能仍知之甚少。在这里，我们首次证明了激活的淋巴细胞中内源性鼠 c-FLIPR 的诱导。为了分析 c-FLIPR 在体内的功能，我们生成了特异性在造血细胞中表达鼠 c-FLIPR 的转基因小鼠。正如预期的那样，来自 c-FLIPR 转基因小鼠的淋巴细胞在体外对 CD95 诱导的凋亡具有抗性。在稳态下，转基因小鼠的细胞数量正常，淋巴器官中 B 细胞和 T 细胞亚群的频率未改变。然而，当受到李斯特菌感染时，与感染的野生型小鼠相比，c-FLIPR 转基因小鼠的肝坏死程度较轻，细菌清除效果更好。我们得出结论，造血细胞中 c-FLIPR 的表达支持针对细菌感染的有效免疫反应。
