Kim K, Lee C K, Sayers T J, Muegge K, Durum S K
Laboratory of Molecular Immunoregulation, Division of Basic Sciences, National Cancer Institute, Frederick, MD 21702, USA.
J Immunol. 1998 Jun 15;160(12):5735-41.
Signals from the IL-7R are essential for normal thymocyte development. We isolated thymocytes from early developmental stages and observed that suspensions of pro-T1, -T2, and -T3 cells rapidly died in culture. Addition of IL-7 promoted their survival, but did not induce cell division. Pro-T4 cells did not undergo rapid cell death, and their survival was therefore independent of IL-7. Death in the absence of IL-7 showed the hallmarks of apoptosis, including DNA fragmentation and annexin V binding; however, caspase inhibitors blocked DNA fragmentation, but did not block cell death. The trophic effect of IL-7 was partially inhibited by blocking protein synthesis. The p53 pathway was not involved in this death pathway, since pro-T cells from p53-/- mice also underwent cell death in the absence of IL-7. The Fas/Fas ligand pathway was not involved in cell death, since Fas-deficient pro-T cells died normally in the absence of IL-7, anti-Fas Abs did not protect cells from death in the absence of IL-7, and Fas expression was undetectable on cells at these stages. The IL-7 trophic affect correlated with increased intracellular levels of Bcl-2 and decreased levels of Bax, whereas no Bcl-X(L), Bcl-w, or Bad was detectable. Thus, maintaining a favorable Bcl-2/Bax ratio may account for the trophic action of IL-7.
IL-7R发出的信号对于正常胸腺细胞发育至关重要。我们从早期发育阶段分离出胸腺细胞，观察到原T1、T2和T3细胞悬液在培养中迅速死亡。添加IL-7可促进它们的存活，但不会诱导细胞分裂。原T4细胞不会发生快速细胞死亡，因此其存活不依赖于IL-7。在没有IL-7的情况下发生的死亡表现出凋亡的特征，包括DNA片段化和膜联蛋白V结合；然而，半胱天冬酶抑制剂可阻断DNA片段化，但不能阻断细胞死亡。通过阻断蛋白质合成可部分抑制IL-7的营养作用。p53途径不参与此死亡途径，因为来自p53基因敲除小鼠的原T细胞在没有IL-7的情况下也会发生细胞死亡。Fas/Fas配体途径不参与细胞死亡，因为Fas缺陷的原T细胞在没有IL-7的情况下正常死亡，抗Fas抗体在没有IL-7的情况下不能保护细胞免于死亡，并且在这些阶段的细胞上未检测到Fas表达。IL-7的营养作用与细胞内Bcl-2水平升高和Bax水平降低相关，而未检测到Bcl-X(L)、Bcl-w或Bad。因此，维持有利的Bcl-2/Bax比率可能解释了IL-7的营养作用。
