Schuler M, Tretter T, Schneller F, Huber C, Peschel C
Department of Medicine III, Johannes Gutenberg University, Mainz, Germany.
Immunobiology. 1999 Feb;200(1):128-39. doi: 10.1016/s0171-2985(99)80038-2.
Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of noncycling B cells in lymphatic and extralymphatic tissues. In the present study we investigated the possible contribution of TGF-beta, as secreted by CLL-B cells, on this low proliferative state. CLL-B cells were shown to express TGF-beta RNA and to release bioactive TGF-beta into culture supernatants. Antibody neutralization of endogenously secreted TGF-beta increased the proliferation of CLL-B cells as cultured in the presence of IL-2 or IL-4 or in direct contact with activated CD4+ T cells. In these culture systems, addition of exogenous TGF-beta downregulated basal and cytokineinduced proliferation of CLL-B cells. In contrast, neither neutralization of endogeneous TGF-beta, nor addition of exogeneous TGF-beta changed the proliferation of CLL-B cells as cultured in the CD40 system. In order to further explore this differential antiproliferative effect of TGF-beta, cytokine secretion of B cells and of CD4+ T cells as well as surface marker expression of CD4+ T cells were assessed in relation to TGF-beta: There was no negative effect of TGF-beta on autocrine secretion of TNF-alpha or sCD23 by CLL-B cells. Unlike tonsillar B cells, CLL-B cells cultured alone or in the CD40 system did no release significant amounts of IL-6 or IL-8 into supernatants. Secretion of IL-2 or IL-4 by activated CD4+ T cells was higher, when T cells were cocultured with normal tonsillar B cells than with CLL-B cells. The amount of IL-2 or IL-4 released by CD4+ T cells cocultured in direct contact with tonsillar or CLL-B cells was not consistently influenced either by neutralization of endogenous TGF-beta or by addition of TGF-beta. Exogenous TGF-beta did not downregulate expression of CD40L, CD27, CD28, CD54 or mTNF-alpha by T helper cells activated with anti-CD3 or PHA. In conclusion, autocrine secretion of TGF-beta exhibits an antiproliferative effect on CLL-B cells. This effect is most relevant in B cells cultured in direct contact with activated CD4+ T cells suggesting an indirect mode of action.
慢性淋巴细胞白血病（CLL）的特征是在淋巴组织和淋巴外组织中积累非循环B细胞。在本研究中，我们调查了CLL-B细胞分泌的转化生长因子-β（TGF-β）对这种低增殖状态可能产生的影响。研究表明，CLL-B细胞表达TGF-β RNA，并将生物活性TGF-β释放到培养上清液中。对内源性分泌的TGF-β进行抗体中和，可增加在IL-2或IL-4存在下培养的CLL-B细胞的增殖，或增加与活化的CD4 + T细胞直接接触时CLL-B细胞的增殖。在这些培养系统中，添加外源性TGF-β可下调CLL-B细胞的基础增殖和细胞因子诱导的增殖。相反，在内源性TGF-β中和或添加外源性TGF-β的情况下，在CD40系统中培养的CLL-B细胞的增殖均未改变。为了进一步探究TGF-β这种不同的抗增殖作用，我们评估了B细胞和CD4 + T细胞的细胞因子分泌以及CD4 + T细胞的表面标志物表达与TGF-β的关系：TGF-β对CLL-B细胞自分泌肿瘤坏死因子-α（TNF-α）或可溶性CD23（sCD23）没有负面影响。与扁桃体B细胞不同，单独培养或在CD40系统中培养的CLL-B细胞不会向上清液中释放大量的白细胞介素-6（IL-6）或白细胞介素-8（IL-8）。当T细胞与正常扁桃体B细胞共培养时，活化的CD4 + T细胞分泌的IL-2或IL-4比与CLL-B细胞共培养时更高。与扁桃体或CLL-B细胞直接接触共培养的CD4 + T细胞释放的IL-2或IL-4量，既不受内源性TGF-β中和的持续影响，也不受TGF-β添加的持续影响。外源性TGF-β不会下调用抗CD3或植物血凝素（PHA）激活的辅助性T细胞上CD40L、CD27、CD28、CD54或膜型肿瘤坏死因子-α（mTNF-α）的表达。总之，TGF-β的自分泌对CLL-B细胞具有抗增殖作用。这种作用在与活化的CD4 + T细胞直接接触培养的B细胞中最为相关，提示其作用方式为间接作用。
