FADD and caspase-8 are required for cytokine-induced proliferation of hemopoietic progenitor cells
FADD and caspase-8 are required for cytokine-induced proliferation of hemopoietic progenitor cells
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DOI：
10.1182/blood-2005-01-0284
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发表时间：
2005-09-01
期刊：
影响因子：
20.3
通讯作者：
Strasser, A
中科院分区：
文献类型：
--
作者：
Pellegrini, M;Bath, S;Strasser, A
Caspase-8及其接头Fas相关死亡结构域(FADD)在淋巴细胞凋亡中的作用已经明确，但它们在其他造血谱系中的作用尚不清楚。我们无法产生在造血细胞中表达FADD或caspase-8显性抑制物的转基因小鼠，可能是因为它们的表达可能阻止了重要造血细胞的产生。当使用逆转录病毒基因传递系统时，表达FADD显性-阴性突变的胎肝干细胞(FADD-DN)在移植到致死照射的小鼠身上时无法产生髓系或淋巴样细胞。然而，表达非常低水平的caspase-8抑制物细胞因子反应修饰物A(CrmA)的胎肝干细胞可以重建造血系统。这种水平的CrmA表达对Fas配体(FasL)诱导的细胞凋亡具有一定的保护作用，并促进骨髓中髓系细胞的聚集，但不抑制丝裂原诱导的B或T淋巴细胞的增殖。利用体外集落形成实验，我们发现表达FADD-dN、CrmA或caspase-8显性阴性突变体的胎肝干细胞不能在细胞因子刺激下增殖。这些数据表明，caspase-8及其接头FADD的酶活性是细胞因子诱导造血祖细胞增殖所必需的。
The role of caspase-8 and its adaptor Fas-assoclated death domain (FADD) in lymphocyte apoptosis is well defined, but their functions in other hemopoietic lineages are not clear. We were unable to generate transgenic mice expressing dominant inhibitors of FADD or caspase-8 in hemopoietic cells, possibly because their expression may have precluded production of vital hemopoietic cells. When using a retroviral gene delivery system, fetal liver stem cells expressing a dominant-negative mutant of FADD (FADD-DN) were unable to generate myeloid or lymphoid cells upon transplantation into lethally irradiated mice. However, fetal liver stem cells expressing very low levels of the caspase-8 inhibitor cytokine response modifier A (CrmA) could reconstitute the hemopoietic system. This level of CrmA expression provided some protection against Fas ligand (FasL)-induced apoptosis and promoted accumulation of myeloid cells in the bone marrow, but it did not inhibit mitogen-induced proliferation of B or T lymphocytes. Using an in vitro colony formation assay, we found that fetal liver stem cells expressing FADD-DN, CrmA, or a dominant-negative mutant of caspase-8 could not proliferate in response to cytokine stimulation. These data demonstrate that the enzymatic activity of caspase-8 and its adaptor FADD are required for cytokine-induced proliferation of hemopoietic progenitor cells.