Transforming growth factor beta as endogenous growth inhibitor of chronic lymphocytic leukemia B cells.
Transforming growth factor beta as endogenous growth inhibitor of chronic lymphocytic leukemia B cells.
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DOI：
10.1084/jem.179.3.999
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发表时间：
1994-03-01
影响因子：
15.3
通讯作者：
Kipps, T J
中科院分区：
文献类型：
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作者：
Lotz, M;Ranheim, E;Kipps, T J
慢性淋巴细胞白血病（CLL） B细胞对体外有丝分裂原和生长因子反应迟钝或难治。本研究探讨了转化生长因子β (tgf - β)，一种有效的淋巴细胞增殖抑制剂，是否在CLL B细胞的生长调节中发挥作用。所有供体的CLL B细胞均表达可检测到的tgf - β 1 mRNA。非刺激培养或细胞表面免疫球蛋白(anti- mu) + phorbol 12-肉豆酸酯13-醋酸酯（PMA）抗体刺激培养的体外tgf - β释放在CLL细胞中高于正常B细胞。在CLL患者的血浆样本中也检测到高水平的tgf - β活性。使用不同的B细胞激活剂检测tgf - β在CLL B细胞生长调节中的作用。来自大多数CLL患者的纯化肿瘤B细胞对抗mu或抗mu + PMA联合反应增殖。CLL B细胞增殖水平低于正常B细胞。一些CLL对这些刺激是不耐受的。CD40抗体可诱导来自所有供体的CLL B细胞在表达CDw32的Fc γ RII L细胞上增殖。在没有或存在额外刺激的情况下，中和tgf - β抗体增加CLL - B细胞增殖。这些效应具有剂量依赖性和特异性。外源性tgf - β完全抑制抗mu、PMA和抗tgf - β诱导的CLL - B细胞增殖。外源性TGF- β可抑制抗cd40诱导的CLL - B细胞增殖。然而，即使在高剂量下，tgf - β也不能完全抑制抗cd40的作用。总之，tgf - β在CLL中过度表达。CLL - B细胞对tgf - β敏感，这种细胞因子作为一种自分泌生长抑制剂，至少部分地解释了这些白血病细胞的增殖反应减少和体内恶性过程的缓慢进展。
Chronic lymphocytic leukemia (CLL) B cells are hyporesponsive or refractory to mitogens and growth factors in vitro. This study examined whether transforming growth factor beta (TGF-beta), a potent inhibitor of lymphocyte proliferation may play a role in the growth regulation of CLL B cells. CLL B cells from all donors treated expressed detectable TGF-beta 1 mRNA. In vitro release of TGF-beta by unstimulated cultures, or cultures stimulated by antibody to cell surface immunoglobulin (anti- mu) plus phorbol 12-myristate 13-acetate (PMA) was higher in CLL than in normal B cells. High levels of TGF-beta activity were also detected in plasma samples of CLL patients. The role of TGF-beta in growth regulation of CLL B cells was tested in assays using different B cell activators. Purified neoplastic B cells from most CLL patients proliferated in response to anti-mu, or the combination of anti-mu plus PMA. Levels of CLL B cell proliferation were lower than observed in normal B cells. Some CLL were refractory to these stimuli. Antibody to CD40 induced proliferation of CLL B cells from all donors tested when presented on Fc gamma RII (CDw32)-expressing L cells. Neutralizing antibodies to TGF-beta increased CLL B cell proliferation in the absence or presence of additional stimuli. These effects were dose dependent and specific. Exogenous TGF-beta completely inhibited CLL B cell proliferation induced by anti-mu, PMA, and anti-TGF-beta. CLL B cell proliferation induced by anti-CD40 was reduced by exogenous TGF- beta. However, even at high doses, TGF-beta did not completely inhibit the anti-CD40 effect. In summary, TGF-beta is overexpressed in CLL. CLL B cells are sensitive to TGF-beta and this cytokine functions as an autocrine growth inhibitor accounting at least in part for reduced proliferative responses of these leukemic cells and for the slow progression of the malignant process in vivo.