Brass U, Tretter T, Schneller F, Schuler M, Huber C, Peschel C
IIIrd Department of Medicine, The Johannes Gutenberg University School of Medicine, Mainz, Germany.
J Interferon Cytokine Res. 1999 Apr;19(4):335-43. doi: 10.1089/107999099314036.
Interferon (IFN)-alpha has a therapeutic effect in several B cell malignancies, including low-grade non-Hodgkin's lymphoma (NHL), multiple myeloma, and hairy cell leukemia, whereas its efficacy in the treatment of B cell chronic lymphocytic leukemia (B-CLL) is rather limited. In the present study, we investigated the effect of IFN-alpha on the biologic functions of B-CLL cells, which were stimulated by cross-linking of the CD40 antigen. In cell samples from 16 B-CLL patients, the addition of IFN-alpha to CD40-stimulated purified B-CLL cells caused a significant increase in [3H]thymidine uptake (p < 0.003). In B-CLL cells maximally activated by CD40 cross-linking and interleukin-2 (IL-2)/IL-10, proliferation was not further enhanced or inhibited by IFN-alpha. In contrast, proliferation of normal tonsillar B cells stimulated by the combination CD40/IL-2/IL-10 was significantly inhibited by IFN-alpha. Because B-CLL activation might be enhanced by induction of the autocrine growth factor tumor necrosis factor-alpha (TNF-alpha), we investigated the effect of IFN-alpha on the secretion of B cell tropic cytokines. In fact, IFN-alpha significantly stimulated the secretion of IL-6 and TNF-alpha in CD40-activated B-CLL cells (p < 0.01). Although exogenous addition of TNF-alpha did not influence activation of CD40-stimulated B-CLL cells, neutralization of TNF-alpha by polyclonal antibodies led to a complete inhibition of CD40-mediated proliferation of B-CLL cells, suggesting that enhanced proliferation and increased cytokine production by CD40-activated B-CLL cells are independent IFN-alpha-mediated events. The studies presented here provide evidence that IFN-alpha mediates costimulatory signals in the context of T cell-mediated B-CLL cell activation.
干扰素（IFN）-α对多种B细胞恶性肿瘤具有治疗作用，包括低度非霍奇金淋巴瘤（NHL）、多发性骨髓瘤和毛细胞白血病，而其在治疗B细胞慢性淋巴细胞白血病（B-CLL）方面的疗效相当有限。在本研究中，我们研究了IFN-α对经CD40抗原交联刺激的B-CLL细胞生物学功能的影响。在16例B-CLL患者的细胞样本中，向经CD40刺激的纯化B-CLL细胞中添加IFN-α导致[3H]胸腺嘧啶核苷摄取显著增加（p<0.003）。在经CD40交联和白细胞介素-2（IL-2）/IL-10最大程度激活的B-CLL细胞中，IFN-α未进一步增强或抑制其增殖。相反，IFN-α显著抑制了由CD40/IL-2/IL-10组合刺激的正常扁桃体B细胞的增殖。由于自分泌生长因子肿瘤坏死因子-α（TNF-α）的诱导可能增强B-CLL的激活，我们研究了IFN-α对B细胞嗜性细胞因子分泌的影响。事实上，IFN-α显著刺激了CD40激活的B-CLL细胞中IL-6和TNF-α的分泌（p<0.01）。虽然外源性添加TNF-α不影响CD40刺激的B-CLL细胞的激活，但多克隆抗体对TNF-α的中和导致CD40介导的B-CLL细胞增殖完全抑制，这表明CD40激活的B-CLL细胞增殖增强和细胞因子产生增加是独立的IFN-α介导事件。本文的研究提供了证据，表明IFN-α在T细胞介导的B-CLL细胞激活过程中介导共刺激信号。
