Louie S W, Ramirez L M, Krieg A M, Maliszewski C R, Bishop G A
Department of Microbiology, University of Iowa, Iowa City 52242.
J Immunol. 1993 Jan 15;150(2):399-406.
The CD5+ B cell lymphoma clone, CH12.LX, endogenously produces IL-4. Blocking the binding of this IL-4 to its cellular receptor inhibited the continuous proliferation of CH12.LX. mAb specific for either IL-4 or the IL-4R profoundly and specifically inhibited the proliferation of CH12.LX cells in a concentration-dependent manner, within 4 h after the addition of mAb. The addition of exogenous rIL-4 alone to CH12.LX cells had no effect on either proliferation or antibody secretion. However, exogenous rIL-4 was able to counteract the effects of anti-IL-4 antibody. Treatment of CH12.LX cells with antisense RNA oligodeoxynucleotides to IL-4 also specifically inhibited cell proliferation and decreased the levels of IL-4 secreted into the culture supernatants by more than 50%, without effect on total RNA or protein synthesis. Effects of antisense IL-4 were also blocked by addition of exogenous IL-4. Control oligodeoxynucleotides of equal size and base composition had no effect, and IL-4 antisense oligodeoxynucleotides did not effect the growth of a B cell lymphoma clone which does not produce IL-4. Blocking the binding of endogenously produced IL-4 to CH12.LX cells did not change the levels of membrane IL-4R or CD5 molecules. However, the constitutive expression of Thy-1 by these B cells was markedly decreased, and anti-Thy-1 antibodies decreased proliferation and PMA-induced aggregation of CH12.LX cells. Autocrine secretion of IL-4 thus appears to be required both for the continuous proliferation of CH12.LX B cells, as well as their expression of Thy-1, which may function either as a homotypic adhesion molecule or a signal transduction molecule for these cells. These findings indicate that endogenously produced lymphokines may play a critical role in the maintenance of B cell hyperproliferative disorders.
CD5+B细胞淋巴瘤克隆CH12.LX可内源性产生白细胞介素-4（IL-4）。阻断这种IL-4与其细胞受体的结合可抑制CH12.LX的持续增殖。针对IL-4或IL-4受体的单克隆抗体（mAb）在添加mAb后4小时内，以浓度依赖的方式深刻且特异性地抑制了CH12.LX细胞的增殖。单独向CH12.LX细胞添加外源性重组IL-4（rIL-4）对增殖或抗体分泌均无影响。然而，外源性rIL-4能够抵消抗IL-4抗体的作用。用针对IL-4的反义RNA寡脱氧核苷酸处理CH12.LX细胞也特异性地抑制了细胞增殖，并使分泌到培养上清液中的IL-4水平降低了50%以上，而对总RNA或蛋白质合成没有影响。添加外源性IL-4也可阻断反义IL-4的作用。等大小和碱基组成的对照寡脱氧核苷酸没有作用，且IL-4反义寡脱氧核苷酸对不产生IL-4的B细胞淋巴瘤克隆的生长没有影响。阻断内源性产生的IL-4与CH12.LX细胞的结合并未改变膜IL-4受体或CD5分子的水平。然而，这些B细胞Thy-1的组成性表达明显降低，抗Thy-1抗体可降低CH12.LX细胞的增殖以及佛波酯（PMA）诱导的聚集。因此，IL-4的自分泌似乎对于CH12.LX B细胞的持续增殖及其Thy-1的表达都是必需的，Thy-1可能作为这些细胞的同型黏附分子或信号转导分子发挥作用。这些发现表明，内源性产生的淋巴因子可能在维持B细胞增殖性疾病中起关键作用。
