BCG-induced interleukin-6 upregulation and BCG internalization in well and poorly differentiated human bladder cancer cell lines.
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.
Bevers
R F
RF
Department of Urology, University of Amsterdam, The Netherlands.
de Boer
E C
EC
Kurth
K H
KH
Schamhart
D H
DH
D000283:Administration, Intravesical; D002454:Cell Differentiation / Q000187:drug effects; D003571:Cytochalasin B / Q000627:therapeutic use; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology*; D009163:Mycobacterium bovis; D010587:Phagocytosis / Q000502:physiology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D001749:Urinary Bladder Neoplasms / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*
D015850:Interleukin-6; D003571:Cytochalasin B