Coral S, Pucillo C, Leonardi A, Fonsatti E, Altomonte M, Maio M
Advanced Immunotherapy Unit, Istituto di Ricovero e Cura a Carattere Scientifico, Aviano, Italy.
Cell Growth Differ. 1997 May;8(5):581-8.
Triggering of HLA class II antigens by the anti-HLA-DR monoclonal antibody (mAb) L243 significantly (P < 0.05) and differentially enhanced the release of tumor necrosis factor alpha (TNF-alpha) by the non-Hodgkin's lymphoma cells Ri-I, Ci-I, and Sc-I, which are at a distinct stage of B-cell differentiation, and by the more mature Burkitt lymphoma cell Raji; in contrast, it did not induce TNF-alpha release by the pre-B leukemia cells Nalm-6 and BV173. TNF-alpha release peaked at 24 h and decreased thereafter, and it was dose dependent and preceded by an increase of TNF-alpha mRNA detectable after 3 h of stimulation with mAb L243. Secreted TNF-alpha mediated the enhancement of nuclear factor kappa B (NF-kappa B) and activator protein-1 (AP-1) binding activity; in fact, the triggering of HLA-DR antigens in the presence of antihuman TNF-alpha-neutralizing antibodies did not upregulate NF-kappa B and AP-1. In contrast, released TNF-alpha was not responsible for the homotypic aggregation of Ri-I, Ci-I, Sc-I, and Raji cells induced by mAb L243, and it did not affect the proliferation of B cells investigated. Altogether, our data demonstrate that: (a) the ability of B cells to release TNF-alpha after triggering of HLA-DR antigens depends on their stage of differentiation; (b) levels of released TNF-alpha seem to correlate with the stage of B-cell maturation but do not correlate with the amounts of cell surface HLA-DR antigens; (c) secreted TNF-alpha regulates the levels of expression of NF-kappa B and AP-1 by an autocrine loop; and (d) intracellular signals mediating TNF-alpha release by B cells are distinct from those regulating homotypic aggregation and proliferation.
抗人 HLA - DR 单克隆抗体（mAb）L243 触发 HLA - II 类抗原，可显著（P < 0.05）且差异性地增强处于 B 细胞分化不同阶段的非霍奇金淋巴瘤细胞 Ri - I、Ci - I 和 Sc - I 以及更成熟的伯基特淋巴瘤细胞 Raji 释放肿瘤坏死因子α（TNF -α）；相比之下，它并未诱导前 B 白血病细胞 Nalm - 6 和 BV173 释放 TNF -α。TNF -α释放在 24 小时达到峰值，之后下降，且呈剂量依赖性，在用 mAb L243 刺激 3 小时后可检测到 TNF -αmRNA 增加，随后才出现 TNF -α释放。分泌的 TNF -α介导了核因子κB（NF -κB）和活化蛋白 -1（AP -1）结合活性的增强；事实上，在存在抗人 TNF -α中和抗体的情况下触发 HLA - DR 抗原并不会上调 NF -κB 和 AP -1。相反，释放的 TNF -α并非 mAb L243 诱导的 Ri - I、Ci - I、Sc - I 和 Raji 细胞同型聚集的原因，并且它不影响所研究 B 细胞的增殖。总之，我们的数据表明：（a）B 细胞在触发 HLA - DR 抗原后释放 TNF -α的能力取决于其分化阶段；（b）释放的 TNF -α水平似乎与 B 细胞成熟阶段相关，但与细胞表面 HLA - DR 抗原的量无关；（c）分泌的 TNF -α通过自分泌环调节 NF -κB 和 AP -1 的表达水平；（d）介导 B 细胞释放 TNF -α的细胞内信号与调节同型聚集和增殖的信号不同。
