Bevers R F, de Boer E C, Kurth K H, Schamhart D H
Department of Urology, University of Amsterdam, The Netherlands.
Eur Cytokine Netw. 1998 Jun;9(2):181-6.
Intravesical bacillus Calmette-Guerin (BCG) is a successful therapy for superficial bladder cancer. However, the working mechanism of BCG after intravesical instillation is not completely understood. A functional role of urothelial (tumor) cells in the initiation of the BCG-induced immune reaction should be considered. Here, the possibility of a causal relationship between BCG-induced interleukin-6 (IL-6) synthesis and BCG internalization by urothelial tumor cells was examined in a series of human transitional bladder cancer (TCC) cell lines with different degrees of differentiation. The results showed that the well differentiated TCC cell lines, RT4, SBC-2, and SBC-7, did not possess the capacity to internalize BCG, which was associated with an inability to upregulate IL-6 synthesis when stimulated with BCG. Moreover, these cell lines expressed a low level of constitutive IL-6 synthesis. In contrast, the poorly differentiated TCC cells, T-24, TCC-SUP and J-82, were able to internalize BCG. In T24 and J82, but not in TCC-SUP cells, BCG internalization appeared to result in an upregulation of IL-6 synthesis. Constitutive IL-6 synthesis of the high grade cell lines was found to be cell line-dependent: both TCC-SUP and J82 cells exhibited a high level of constitutive IL-6 synthesis, whereas T24 cells exhibited a low level. The possible relationship between BCG internalization and IL-6 upregulation was studied in detail with the T24 cell line, which exhibited a low constitutive and high BCG-inducible IL-6 synthesis, using anti-BCG antibodies (alphaBCG) and Cytochalasin B as internalization inhibitors. Upregulation of IL-6 synthesis was significantly inhibited by alphaBCG or Cytochalasin B, indicating that internalization is a prerequisite for BCG-induced upregulation of IL-6 synthesis. In conclusion, upregulation of IL-6 production due to BCG internalization by poorly differentiated bladder carcinoma cells may be part of the mode of action of intravesical BCG therapy.
膀胱内灌注卡介苗（BCG）是浅表性膀胱癌的一种成功治疗方法。然而，膀胱内灌注后BCG的作用机制尚未完全明确。应考虑尿路上皮（肿瘤）细胞在BCG诱导的免疫反应起始过程中的功能作用。在此，我们在一系列具有不同分化程度的人移行性膀胱癌（TCC）细胞系中，研究了BCG诱导的白细胞介素-6（IL-6）合成与尿路上皮肿瘤细胞内化BCG之间因果关系的可能性。结果显示，高分化的TCC细胞系RT4、SBC-2和SBC-7不具备内化BCG的能力，这与用BCG刺激时无法上调IL-6合成有关。此外，这些细胞系组成性IL-6合成水平较低。相比之下，低分化的TCC细胞T-24、TCC-SUP和J-82能够内化BCG。在T24和J82细胞中，但不是在TCC-SUP细胞中，BCG内化似乎导致IL-6合成上调。发现高分级细胞系的组成性IL-6合成具有细胞系依赖性：TCC-SUP和J82细胞均表现出高水平的组成性IL-6合成，而T24细胞表现出低水平。使用抗BCG抗体（αBCG）和细胞松弛素B作为内化抑制剂，在T24细胞系中详细研究了BCG内化与IL-6上调之间的可能关系，T24细胞系组成性IL-6合成水平低但BCG诱导的IL-6合成水平高。αBCG或细胞松弛素B显著抑制了IL-6合成的上调，表明内化是BCG诱导IL-6合成上调的先决条件。总之，低分化膀胱癌细胞内化BCG导致IL-6产生上调可能是膀胱内BCG治疗作用模式的一部分。
