The essential role of interferon-gamma during interleukin-12 therapy for murine transitional cell carcinoma of the bladder.

Abstract

PURPOSE:

Recombinant interleukin (IL)-12 and adenoviral IL-12 gene therapy have been shown to be potent therapeutic interventions for murine transitional cell carcinoma (TCC) of the bladder in vivo. We investigated the mechanisms through which IL-12 induces antibladder cancer immunity.

MATERIALS AND METHODS:

The ability of IL-12 to enhance interferon-gamma (IFN-gamma) expression, a major T-helper type 1 cytokine, was analyzed in murine serum, urine and splenocyte cultures. MB49, a murine TCC line, was treated with IFN-gamma and evaluated for its proliferation, surface molecule expression and sensitivity to splenocyte mediated cytotoxicity. Neutralizing antiIFN-gamma antibody was applied to test the role of IFN-gamma in the IL-12 therapy of MB49 tumor.

RESULTS:

IL-12 was observed to significantly increase IFN-gamma concentrations in serum and urine as well as in splenocyte cultures. While IL-12 had no direct activity against TCC in vitro, IFN-gamma showed potent dose dependent antiproliferative and pro-apoptotic activity, which was further enhanced by supplementation of tumor necrosis factor-alpha. In addition, IFN-gamma substantially up-regulated the expression of surface immune molecules on TCC cells, including MHC-I, MHC-II, ICAM-I, B7.1, B7.2 and Fas. Maximum splenocyte mediated cytotoxicity against TCC was enhanced by pretreatment of target bladder cancer cells with IFN-gamma plus tumor necrosis factor-alpha. Furthermore, IL-2 in combination with IL-12 further enhanced splenocyte mediated cytotoxicity. The in vivo antibladder cancer activity of IL-12 was abolished by concurrent treatment with antibodies to IFN-gamma.

CONCLUSIONS:

This study strongly suggests that IFN-gamma has an essential role in IL-12 induced antibladder tumor immunity. Activation of host effector immune cells by IL-12 is also required for induction of optimal tumor destruction in IL-12 therapy.

• Authors: Michael A O'Donnell, Yi Luo, Sharon E Hunter, Xiaohong Chen, Lori L Hayes, Steven K Clinton
• Journal: The Journal of urology (J Urol) Vol. 171 Issue 3 Pg. 1336-42 (Mar 2004) ISSN: 0022-5347 [Print] United States
• PMID: 14767344 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• fas Receptor
• Interleukin-12
• Interferon-gamma

Topics

• Animals
• Carcinoma, Transitional Cell (drug therapy, immunology, pathology)
• Cell Division
• Cell Line, Tumor
• Interferon-gamma (therapeutic use)
• Interleukin-12 (therapeutic use)
• Mice
• Mice, Inbred C3H
• Mice, Inbred C57BL
• Spleen (cytology, immunology)
• Urinary Bladder Neoplasms (drug therapy, immunology, pathology)
• fas Receptor (immunology)