De Maria R, Testa U, Luchetti L, Zeuner A, Stassi G, Pelosi E, Riccioni R, Felli N, Samoggia P, Peschle C
Department of Hematology-Oncology, Istituto Superiore di Sanita', Rome, Italy.
Blood. 1999 Feb 1;93(3):796-803.
The possible involvement of Fas and Fas ligand (FasL) in the regulation of erythropoiesis was evaluated. Immunohistochemistry of normal bone marrow specimens revealed that several immature erythroblasts undergo apoptosis in vivo. Analysis of bone marrow erythroblasts and purified progenitors undergoing unilineage erythroid differentiation showed that Fas is rapidly upregulated in early erythroblasts and expressed at high levels through terminal maturation. However, Fas crosslinking was effective only in less mature erythroblasts, particularly at basophilic level, where it induced apoptosis antagonized by high levels of erythropoietin (Epo). In contrast, FasL was selectively induced in late differentiating Fas-insensitive erythroblasts, mostly at the orthochromatic stage. FasL is functional in mature erythroblasts, as it was able to kill Fas-sensitive lymphoblast targets in a Fas-dependent manner. Importantly, FasL-bearing mature erythroblasts displayed a Fas-based cytotoxicity against immature erythroblasts, which was abrogated by high levels of Epo. These findings suggest the existence of a negative regulatory feedback between mature and immature erythroid cells, whereby the former cell population might exert a cytotoxic effect on the latter one in the erythroblastic island. Hypothetically, this negative feedback operates at low Epo levels to moderate the erythropoietic rate; however, it is gradually inhibited at increasing Epo concentrations coupled with enhanced erythrocyte production. Thus, the interaction of Fas and FasL may represent an apoptotic control mechanism for erythropoiesis, contributing to the regulation of red blood cell homeostasis.
评估了Fas和Fas配体（FasL）在红细胞生成调节中的可能作用。对正常骨髓标本进行免疫组织化学分析显示，体内有几个未成熟的成红细胞发生凋亡。对骨髓成红细胞和经历单系红细胞分化的纯化祖细胞进行分析表明，Fas在早期成红细胞中迅速上调，并在终末成熟过程中高水平表达。然而，Fas交联仅在不太成熟的成红细胞中有效，特别是在嗜碱性阶段，在此阶段它诱导的凋亡被高水平的促红细胞生成素（Epo）所拮抗。相反，FasL在晚期分化的对Fas不敏感的成红细胞中选择性诱导，主要在正染阶段。FasL在成熟成红细胞中具有功能，因为它能够以Fas依赖的方式杀死对Fas敏感的淋巴细胞靶细胞。重要的是，携带FasL的成熟成红细胞对未成熟成红细胞表现出基于Fas的细胞毒性，而高水平的Epo可消除这种毒性。这些发现表明在成熟和未成熟红细胞之间存在负调节反馈，据此前一种细胞群体可能在成红细胞岛中对后一种细胞群体发挥细胞毒性作用。假设这种负反馈在低Epo水平下起作用以调节红细胞生成率；然而，在Epo浓度增加并伴有红细胞生成增强时，它会逐渐受到抑制。因此，Fas和FasL的相互作用可能代表红细胞生成的一种凋亡控制机制，有助于调节红细胞内环境稳定。
