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Lookup NU author(s): Simon Dovedi,
Emeritus Professor John Kirby,
Dr Helen Maitland,
Dr Barry Davies,
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Purpose: Intravesical bacillus Calmette-Guerin (BCG) therapy is the principal treatment for high risk, noninvasive urothelial carcinoma and carcinoma in situ of the bladder. However, up to 40% of patients fail to respond to this treatment. In this study the potential for inhibition of PGE 2 production by BCG treated dendritic cells (DCs) was studied in the context of preferential polarization of the immune response toward a cancer clearing T-helper type 1 immune response. Materials and Methods: Murine bone marrow derived DCs were cultured with interleukin (IL)-4 and granulocyte-macrophage colony-stimulating factor. After 7 days the cells were stimulated with BCG. Cell surface expression of co-stimulatory molecules and phagocytic ability were measured by flow cytometry analysis to verify cell activation. The production of IL-10 and IL-12 was measured after DC stimulation with BCG in the presence of IL-10, prostaglandin E2 (Cayman Chemical, Ann Arbor, Michigan), antiIL-10 antibody (Insight Biotechnology, Wembley, United Kingdom), NS-398 and indomethacin (Sigma, Poole, United Kingdom). Results: Prostaglandin E2 stimulated a dose dependent increase in the levels of IL-10 produced by BCG activated DCs (p < 0.01). IL-10 significantly decreased IL-12 production (p < 0.001), while IL-10 blockade significantly increased IL-12 levels (p < 0.05). The COX-2 selective inhibitor NS-398 caused a dose dependent increase in the concentration of IL-12 produced by BCG activated DCs (p < 0.01). This effect was also seen with the partially selective COX-1 inhibitor indomethacin (p < 0.05). Conclusions: The inhibition of PGE2 synthesis by COX inhibition favored the production of IL-12 by BCG activated DC. This potentially will result in the generation of a T-helper type 1, polarized T-cell response that may improve the efficacy of BCG therapy. Copyright © 2005 by American Urological Association.
Author(s): Dovedi SJ, Kirby JA, Atkins H, Davies BR, Kelly JD
Publication type: Article
Publication status: Published
Journal: The Journal of Urology
ISSN (print): 0022-5347
ISSN (electronic): 1527-3792
Publisher: Elsevier Inc.
PubMed id: 15947685
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