Journal article
The essential role of interferon-gamma during interleukin-12 therapy for murine transitional cell carcinoma of the bladder
The Journal of urology, Vol.171(3), pp.1336-1342
03/2004
DOI: 10.1097/01.ju.0000109751.60921.da
PMID: 14767344
Abstract
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.
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.
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.
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.
Details
- Title: Subtitle
- The essential role of interferon-gamma during interleukin-12 therapy for murine transitional cell carcinoma of the bladder
- Creators
- Michael A O'Donnell - University of IowaYi Luo - The Ohio State UniversitySharon E Hunter - The Ohio State UniversityXiaohong Chen - The Ohio State UniversityLori L Hayes - The Ohio State UniversitySteven K Clinton - The Ohio State University
- Resource Type
- Journal article
- Publication Details
- The Journal of urology, Vol.171(3), pp.1336-1342
- DOI
- 10.1097/01.ju.0000109751.60921.da
- PMID
- 14767344
- ISSN
- 0022-5347
- eISSN
- 1527-3792
- Grant note
- R29 CA64230 / NCI NIH HHS K07 CA23326 / NCI NIH HHS
- Language
- English
- Date published
- 03/2004
- Academic Unit
- Urology
- Record Identifier
- 9984320852902771
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