Role of Th1-stimulating cytokines in bacillus Calmette-Guérin (BCG)-induced macrophage cytotoxicity against mouse bladder cancer MBT-2 cells

Y Luo; H Yamada; D P Evanoff; X Chen

doi:10.1111/j.1365-2249.2006.03191.x

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Role of Th1-stimulating cytokines in bacillus Calmette-Guérin (BCG)-induced macrophage cytotoxicity against mouse bladder cancer MBT-2 cells

Journal article

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Role of Th1-stimulating cytokines in bacillus Calmette-Guérin (BCG)-induced macrophage cytotoxicity against mouse bladder cancer MBT-2 cells

Y Luo, H Yamada, D P Evanoff and X Chen

Clinical and experimental immunology, Vol.146(1), pp.181-188

10/2006

DOI: 10.1111/j.1365-2249.2006.03191.x

PMCID: PMC1809722

PMID: 16968412

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Abstract

Previously, we have demonstrated that macrophages exhibited cytotoxicity toward mouse bladder cancer MBT-2 cells upon bacille Calmette-Guérin (BCG) stimulation. In this study, we have investigated the role of Th1-stimulating cytokines in BCG-induced macrophage cytotoxicity. Thioglycollate-elicited peritoneal exudate cells (PECs) were used as a conventional source for macrophages and the induction of PEC effector functions (cytolytic activity and cytokine production) by BCG was evaluated in vitro. The BCG-activated PECs showed potent cytotoxicity and killed MBT-2 cells in a dose-dependent manner. Depletion of T cells, natural killer (NK) cells, or both, in PEC preparations exhibited a marginal or small reduction of MBT-2 cell killing, suggesting that macrophages played a primary role in PEC cytotoxicity. Transwell assays indicated that the maximal PEC cytotoxicity required both direct cell-cell contact and soluble factors such as interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha. Neutralizing endogenous cytokines interleukin (IL)-12, IL-18, IFN-gamma or TNF-alpha reduced PEC cytotoxicity by 38%, 22%, 15% and 94%, respectively. Supplementation of BCG with recombinant (r)IL-2, rIL-12 or rIL-18 increased PEC cytotoxicity by approximately twofold. Compared with control BCG for PEC stimulation, rBCGs expressing IL-2 or IL-18 showed enhanced MBT-2 cell killing by PECs. Increased cytokine production (IFN-gamma, TNF-alpha and IL-6) was also observed in rBCG-stimulated PEC cultures. Taken together, these results suggest that Th1-stimulating cytokines play an important role in BCG-induced macrophage cytotoxicity and that combination of BCG with selected Th1-stimulating cytokines, either supplemented or expressed by BCG, may enhance the effect of BCG in the treatment of bladder cancer patients.

Animals

BCG Vaccine - immunology

Cell Death - immunology

Cytokines - biosynthesis

Cytokines - immunology

Cytotoxicity, Immunologic

Female

Macrophage Activation - immunology

Macrophages, Peritoneal - immunology

Mice

Mice, Inbred C3H

Recombinant Proteins - immunology

Th1 Cells - immunology

Tumor Cells, Cultured

Up-Regulation - immunology

Urinary Bladder Neoplasms - immunology

Urinary Bladder Neoplasms - pathology

Details

Title: Subtitle: Role of Th1-stimulating cytokines in bacillus Calmette-Guérin (BCG)-induced macrophage cytotoxicity against mouse bladder cancer MBT-2 cells
Creators: Y Luo - University of Iowa
H Yamada - University of Iowa
D P Evanoff - University of Iowa
X Chen - University of Iowa
Resource Type: Journal article
Publication Details: Clinical and experimental immunology, Vol.146(1), pp.181-188
DOI: 10.1111/j.1365-2249.2006.03191.x
PMID: 16968412
PMCID: PMC1809722
NLM abbreviation: Clin Exp Immunol
ISSN: 0009-9104
eISSN: 1365-2249
Grant note: R21CA104308 / NCI NIH HHS R21 CA104308 / NCI NIH HHS
Language: English
Date published: 10/2006
Academic Unit: Urology; Internal Medicine
Record Identifier: 9984320062502771

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