Importance of urinary interleukin-18 in intravesical immunotherapy with bacillus Calmette-Guérin for superficial bladder tumors

Objective: Intravesical immunotherapy with bacillus Calmette-Guérin (BCG) remains the most efficient modality for the treatment of carcinoma in situ and prevention of recurrences of Ta and T1 bladder tumors. Although elevations in a variety of urinary cytokines have been reported after BCG instillation, the mechanism by which BCG mediates antitumor activity has not been clearly established. Based upon our murine study (J Urol 2000;163:1549-1552), we reevaluated urinary cytokines before and after BCG instillations from the point of T helper (Th) 1/2 lymphocyte cytokine profiles. Methods: Urinary interleukin (IL)-2, interferon (IFN)-γ, IL-12, and IL-18 for Th1, and IL-4 for Th2 cytokines were measured by enzyme-linked immunosorbent assay just before and 4 h after the 4th or 5th instillation of 8 weekly instillations of 40-80 mg BCG, Tokyo strain, in 12 patients with superficial stages Ta and T1 bladder cancer, and carcinoma in situ. Results: Two representative Th1 cytokines, IL-2 and IFN-γ, significantly increased in urine after intravesical BCG instillations. Interestingly, IL-12, a strong inducer of Th1 cytokines, did not increase in the urine after BCG instillations. Instead, IL-18, that has recently been reported to induce IFN-γ production in T and NK cells in synergy with IL-12, obviously elevated in urine after BCG instillations. Urinary IL-4, a representative of Th2 cytokines, did not change at all after intravesical BCG instillations. Conclusion: Our results clearly show the predominant importance of IL-18 followed by increases in Th1 cytokines, such as IL-2 and IFN-γ, in the mechanisms of intravesical immunotherapy with BCG.