Interleukin-10 inhibits Mycobacterium bovis bacillus Calmette-Guérin (BCG)-induced macrophage cytotoxicity against bladder cancer cells.
The mechanisms underlying bacillus Calmette-Guérin (BCG) immunotherapy of bladder cancer currently remain elusive. Previously, we demonstrated that macrophages were cytotoxic to bladder cancer cells upon BCG stimulation in vitro. However, macrophages from C57BL/6 mice were less potent than those from C3H/HeN mice for the killing of bladder cancer cells. This study was to determine whether interleukin (IL)-10 produced by macrophages in response to BCG is a causative factor for the reduced cytotoxicity in BCG-stimulated C57BL/6 macrophages. Thioglycollate-elicited peritoneal macrophages were prepared and analysed for the BCG induction of cytotoxicity, cytokines and nitric oxide (NO) in vitro. Compared to BCG-stimulated C3H/HeN macrophages, BCG-stimulated C57BL/6 macrophages exhibited reduced killing of bladder cancer MBT-2 cells and MB49 cells. Studies demonstrated further that BCG-stimulated C57BL/6 macrophages produced a high level of IL-10, which correlated with reduced production of tumour necrosis factor (TNF)-alpha, IL-6 and NO. Neutralizing endogenous IL-10 during BCG stimulation increased C57BL/6 macrophage cytotoxicity against MB49 cells by 3.2-fold, along with increased production of TNF-alpha by 6.4-fold and NO by 3.6-fold, respectively. Macrophages from C57BL/6 IL-10(-/-) mice also exhibited increased killing of MB49 cells and production of TNF-alpha and NO upon BCG stimulation. In addition, supplementation of exogenous recombinant IL-10 reduced BCG-induced C3H/HeN macrophage cytotoxicity against both MBT-2 cells and MB49 cells in a dose-dependent manner. These results reveal the inhibitory role of IL-10 in BCG-induced macrophage cytotoxicity, suggesting that blockage of IL-10 may potentially enhance the effect of BCG in the treatment of bladder cancer patients.
Department of Urology, University of Iowa, Iowa City, Iowa 52242, USA. yi-luo@uiowa.edu
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Luo
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Han
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Evanoff
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Chen
D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D008262:Macrophage Activation / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009163:Mycobacterium bovis / Q000276:immunology*; D009569:Nitric Oxide / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology; D001749:Urinary Bladder Neoplasms / Q000276:immunology* / Q000628:therapy
D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D009569:Nitric Oxide