Foa R, Massaia M, Cardona S, Tos A G, Bianchi A, Attisano C, Guarini A, di Celle P F, Fierro M T
Dipartimento di Scienze Biomediche e Oncologia Umana, University of Torino, Italy.
Blood. 1990 Jul 15;76(2):393-400.
Tumor necrosis factor-alpha (TNF) is a cytokine that displays a pleomorphic array of effects on different cell populations. Evidence is presented that TNF may be constitutively produced by B-cell chronic lymphocytic leukemia (B-CLL) and hairy cell leukemia (HCL) cells and that it may play a relevant role in these diseases. These conclusions are based on the presence of circulating levels of TNF in the serum of 20 of the 24 patients tested (83.3%), while undetectable values were found in normal sera. The suggestion that the increased serum levels were due to the leukemic cell population is strengthened by the evidence that purified B-CLL and HCL cells may constitutively release variable degrees of TNF. These levels markedly increase after incubation with interferon gamma or phytohemagglutinin (PHA) plus phorbol myristate acetate (PMA). The cellular release of TNF by primary B-CLL cells was significantly (P less than .001) higher in B-CLL stage O-I patients compared with stage II-III patients. The demonstration that, in B-cell chronic lymphoproliferative disorders, the pathologic cells may release TNF was further confirmed by the presence of the mRNA for this cytokine in primary and/or in pre-activated cells. Recombinant TNF was capable of inducing a proliferative signal only in a minority of cases (4/24); in most cases it was ineffective, and, in a few, it reduced the degree of proliferation. Furthermore, in costimulatory experiments with interleukin-2 and PHA plus PMA, TNF was ineffective. On the other hand, when primary B-CLL cells were incubated in the presence of an anti-TNF antibody, in 8 of 12 independent experiments a 2- to 15-fold increase in thymidine uptake was documented. Taken together, these results suggest that TNF may play a regulatory role in the progression of the neoplastic clone in B-cell chronic lymphoproliferative disorders and may be implicated in some of the side effects associated with these diseases.
肿瘤坏死因子-α（TNF）是一种细胞因子，对不同细胞群体具有多种效应。有证据表明，TNF可能由B细胞慢性淋巴细胞白血病（B-CLL）和毛细胞白血病（HCL）细胞组成性产生，并且可能在这些疾病中发挥相关作用。这些结论基于在24例受测患者中的20例（83.3%）血清中检测到循环水平的TNF，而在正常血清中未检测到该值。纯化的B-CLL和HCL细胞可能组成性释放不同程度的TNF，这一证据进一步支持了血清水平升高是由于白血病细胞群体所致的观点。与干扰素γ或植物血凝素（PHA）加佛波醇肉豆蔻酸酯乙酸酯（PMA）孵育后，这些水平显著增加。与II-III期患者相比，O-I期B-CLL患者的原代B-CLL细胞释放TNF的水平显著更高（P小于0.001）。在B细胞慢性淋巴细胞增殖性疾病中，病理细胞可能释放TNF这一现象，通过该细胞因子的mRNA在原代和/或预激活细胞中的存在得到进一步证实。重组TNF仅在少数情况下（4/24）能够诱导增殖信号；在大多数情况下它无效，并且在少数情况下，它会降低增殖程度。此外，在与白细胞介素-2以及PHA加PMA的共刺激实验中，TNF无效。另一方面，当原代B-CLL细胞在抗TNF抗体存在的情况下孵育时，在12个独立实验中的8个实验中记录到胸苷摄取增加了2至15倍。综上所述，这些结果表明TNF可能在B细胞慢性淋巴细胞增殖性疾病中肿瘤克隆的进展中发挥调节作用，并且可能与这些疾病相关的一些副作用有关。
