Heinrich M C, Dooley D C, Keeble W W
Department of Medicine, Oregon Health Sciences University, Portland, USA.
Blood. 1995 Apr 1;85(7):1769-80.
Transforming growth factor beta 1 (TGF-beta 1), a product of marrow stromal cells, inhibits the proliferation and differentiation of hematopoietic progenitor cells within the hematopoietic microenvironment. Steel factor (SF), also a product of marrow stromal cells, is an essential positive regulator of hematopoiesis in vivo. TGF-beta 1 has been shown to repress human and murine leukemic cell and murine lin- bone marrow mononuclear cell expression of the receptor for SF (c-kit). We speculated that TGF-beta 1 might exert its inhibitory effect on hematopoiesis in part by decreasing SF/c-kit interactions. Therefore, we tested the hypothesis that TGF-beta 1 inhibits both stromal cell expression of SF and hematopoietic progenitor cell expression of c-kit. We measured stromal cell expression of SF protein and hematopoietic progenitor cell expression of membrane-bound c-kit before and after exposure to recombinant human TGF-beta 1. Both stromal cell expression of SF protein and hematopoietic progenitor cell expression of c-kit protein were inhibited 50% to 80% by TGF-beta 1. Using Northern blot and ribonuclease protection assays, we determined that TGF-beta 1 repressed stromal cell SF mRNA, but did not alter SF transcript stability. TGF-beta 1 was also found to repress c-kit mRNA in human leukemic myeloblasts as well as in normal lin- hematopoietic progenitor cells. In contrast with its effect on SF mRNA, TGF-beta 1 accelerated the degradation of c-kit mRNA. We conclude that TGF-beta 1 inhibits stromal cell production of SF by repression of SF gene transcription and represses hematopoietic progenitor cell expression of c-kit by decreasing the stability of c-kit transcripts. Taking into account the importance of SF and c-kit in maintaining steady-state hematopoiesis in vivo, the dual effect of TGF-beta 1 on both SF and c-kit gene expression is likely to be one of the major mechanisms by which TGF-beta 1 inhibits hematopoiesis in vivo.
转化生长因子β1（TGF-β1）是骨髓基质细胞的产物，可抑制造血微环境中造血祖细胞的增殖和分化。Steel因子（SF）同样是骨髓基质细胞的产物，是体内造血过程中一种重要的正向调节因子。已有研究表明，TGF-β1可抑制人及小鼠白血病细胞以及小鼠lin-骨髓单个核细胞中SF受体（c-kit）的表达。我们推测，TGF-β1可能部分通过减少SF/c-kit相互作用来发挥其对造血的抑制作用。因此，我们检验了TGF-β1既抑制基质细胞SF表达又抑制造血祖细胞c-kit表达这一假说。我们检测了重组人TGF-β1作用前后基质细胞SF蛋白的表达以及造血祖细胞膜结合型c-kit的表达。TGF-β1使基质细胞SF蛋白表达和造血祖细胞c-kit蛋白表达均受到50%至80%的抑制。通过Northern印迹法和核糖核酸酶保护分析，我们确定TGF-β1可抑制基质细胞SF mRNA，但不改变SF转录本的稳定性。同时还发现TGF-β1可抑制人白血病原粒细胞以及正常lin-造血祖细胞中c-kit mRNA的表达。与对SF mRNA的作用相反，TGF-β1加速了c-kit mRNA的降解。我们得出结论，TGF-β1通过抑制SF基因转录来抑制基质细胞产生SF，并通过降低c-kit转录本的稳定性来抑制造血祖细胞c-kit的表达。考虑到SF和c-kit在维持体内稳态造血中的重要性，TGF-β1对SF和c-kit基因表达的双重作用可能是其在体内抑制造血的主要机制之一。
