The essential role of interferon-gamma during interleukin-12 therapy for murine transitional cell carcinoma of the bladder.
| Autor: | O'Donnell MA; Department of Urology, University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242, USA. odonnell@uiowa.edu, Luo Y, Hunter SE, Chen X, Hayes LL, Clinton SK |
|---|---|
| Jazyk: | angličtina |
| Zdroj: | The Journal of urology [J Urol] 2004 Mar; Vol. 171 (3), pp. 1336-42. |
| DOI: | 10.1097/01.ju.0000109751.60921.da |
| Abstrakt: | 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. |
| Databáze: | MEDLINE |
| Externí odkaz: |
|