REGULATION OF NORMAL AND NEOPLASTIC HEMATOPOIETIC CELL GROWTH--ROLE OF BRMS

研究淋巴造血细胞生长的体液调节 和分化以及成熟的细胞功能，我们发现 转化生长因子β具有很强的双功能作用。转化生长因子 β1和转化生长因子β2是等效性的选择性抑制剂 阻止早期人类和小鼠生长的造血术 祖细胞，但不是更差异化的祖细胞。部分使用 纯化的小鼠造血干细胞在单细胞检测中的应用 几种细胞因子，表明转化生长因子β直接作用于血管内皮细胞 阻止生长的细胞。相反，在GM-CSF中添加转化生长因子β 刺激的骨髓细胞极大地促进了生长，导致 主要是由于粒细胞的增加，也被证明有 在单细胞分析中的直接影响。无论是体内还是体外 用转化生长因子β进行的实验表明，造血干细胞 可逆地阻止进入细胞周期。这些增长 调节效应至少在两个水平上起作用：1)反式下调 细胞表面受体对正向调节信号的调制 和/或2)干扰这些分子的受体后信号 通过减少细胞因子介导的磷酸化或通过抑制 特定的基因表达。白血病细胞株可能是敏感的 或对转化生长因子β介导的生长抑制不敏感。增长 肿瘤B淋巴细胞可通过逃逸转化生长因子β介导的途径发生 自分泌抑制环。激活信号(例如佛波酯)可以 通过刺激活性转化生长因子β的产生抑制肿瘤细胞生长 诱导细胞表面表达功能性转化生长因子β 感受器。CD3+和CD3-在研究效应细胞功能中的作用 淋巴细胞，发现细胞介导的细胞毒作用要大得多 对转化生长因子β介导的抑制比细胞生长更敏感 转化生长因子β抑制IL-2受体p55链的表达 P75 IL-2受体链无表达。

In studying the humoral regulation of lymphohematopoietic cell growth and differentiation as well as mature cell function, we have found that transforming growth factor Beta has potent bifunctional effects. TGF Beta 1 and TGF Beta 2 are equipotent selective inhibitors of hematopoiesis that halt the growth of early human and murine progenitors, but not more differentiated progenitors. Using partially purified murine hematopoietic stem cells in single cell assays with several cytokines, it was shown that TGF Beta acted directly on the cells to block growth. In contrast, addition of TGF Beta to GM-CSF stimulated bone marrow cells greatly augmented growth, leading predominantly to an increase in granulocytes, and was also shown to have a direct effect in single cell assays. Both in vivo and in vitro experiments with TGF Beta show that the hematopoietic stem cells are reversibly prevented from entering the cell cycle. These growth modulatory effects function at, at least, two levels: 1) trans-down modulation of the cell surface receptors for positive regulatory signals and/or 2) interfering with post-receptor signalling of these molecules by decreasing cytokine mediated phosphorylation or by inhibiting specific gene expression. Leukemic cell lines could be either sensitive or insensitive to TGF Beta mediated growth inhibition. Growth of neoplastic B lymphocytes can occur by escaping from a TGF Beta mediated autocrine inhibitory loop. Activation signals (e.g. phorbol esters) can inhibit tumor cell growth by stimulation of active TGF Beta production and induction of cell surface expression of functional TGF Beta receptors. In studying effector cell function by CD3+ and CD3- lymphocytes, it was found that cell mediated cytotoxicity was much more sensitive to TGF Beta mediated inhibition than cell growth and that expression of the IL 2 receptor p55 chain was inhibited by TGF Beta while expression of p75 IL 2 receptor chain was not.