Jacobsen S E, Jacobsen F W, Fahlman C, Rusten L S
Department of Immunology, Norwegian Radium Hospital, Oslo.
Stem Cells. 1994;12 Suppl 1:111-26; discussion 126-8.
The clinical application of tumor necrosis factor-alpha (TNF-alpha) has so far been limited due to the severe adverse effects associated with its systemic use. Recently, two distinct TNF receptors with molecular weights of 55 kDa (TNFR55) and 75 kDa (TNFR75) have been cloned and characterized. The subsequent development of TNF-alpha mutants with selective activity on either TNFR55 or TNFR75 suggest that such mutants might maintain the therapeutic (anti-tumor) potential of wild type TNF-alpha, but exhibit reduced toxicity (proinflammatory effects). In the present article we discuss previous studies on the effects of TNF-alpha in in vitro and in vivo hematopoiesis. In addition, we summarize more recent data from our laboratory as well as others, elucidating the role of TNF-alpha as a direct bifunctional regulator of in vitro hematopoiesis. Specifically, TNF-alpha is a potent inhibitor of the clonal growth of primitive and committed murine and human bone marrow progenitors in combination with multiple cytokines, including granulocyte colony-stimulating factor (G-CSF), CSF-1, erythropoietin (Epo), stem cell factor (SCF), and flt3 ligand (FL). In contrast, TNF-alpha at low concentrations can synergistically and directly enhance the clonal growth of primitive and more mature human CD34+ bone marrow progenitors when combined with GM-CSF or interleukin (IL)-3. Thus, a critical determinant of whether TNF-alpha elicits a stimulatory or inhibitory effect on the in vitro growth of hematopoietic progenitors appears to be the specific growth factors with which it interacts, rather than the maturity of the targeted progenitor. Furthermore, we describe the involvement of the two TNF receptors in signaling in vitro hematopoietic effects of TNF-alpha. Whereas TNFR55 is involved in most observed responses to TNF-alpha, signaling of TNFR75 appears to be restricted to inhibitory effects on primitive progenitors. Finally, we discuss the complexity of direct and indirect actions of TNF-alpha in in vivo hematopoiesis, and the potential clinical applications of TNF-alpha or TNF mutants.
由于肿瘤坏死因子-α（TNF-α）全身应用会产生严重不良反应，其临床应用至今仍受到限制。最近，已克隆并鉴定出两种分子量分别为55 kDa（TNFR55）和75 kDa（TNFR75）的不同TNF受体。随后开发出对TNFR55或TNFR75具有选择性活性的TNF-α突变体，这表明此类突变体可能保留野生型TNF-α的治疗（抗肿瘤）潜力，但毒性（促炎作用）降低。在本文中，我们讨论了以往关于TNF-α在体外和体内造血作用的研究。此外，我们总结了来自我们实验室及其他实验室的最新数据，阐明了TNF-α作为体外造血直接双功能调节因子的作用。具体而言，TNF-α与多种细胞因子联合使用时，是原始及定向的小鼠和人类骨髓祖细胞克隆生长的强效抑制剂，这些细胞因子包括粒细胞集落刺激因子（G-CSF）、CSF-1、促红细胞生成素（Epo）、干细胞因子（SCF）和flt3配体（FL）。相比之下，低浓度的TNF-α与GM-CSF或白细胞介素（IL）-3联合使用时，可协同并直接增强原始及更成熟的人类CD34+骨髓祖细胞的克隆生长。因此，TNF-α对造血祖细胞体外生长产生刺激或抑制作用的关键决定因素似乎是与其相互作用的特定生长因子，而非靶向祖细胞的成熟度。此外，我们描述了两种TNF受体在TNF-α体外造血作用信号传导中的参与情况。虽然TNFR55参与了大多数观察到的对TNF-α的反应，但TNFR75的信号传导似乎仅限于对原始祖细胞的抑制作用。最后，我们讨论了TNF-α在体内造血中直接和间接作用的复杂性，以及TNF-α或TNF突变体的潜在临床应用。
