Et-11 analysis of anti-glioma effect by proinflammatory cytokines

Abstract OBJECT Antiglioma activity of proinflammatory cytokines, (TNF-alpha, IL-2, IL-12 related cytokines, IL-18, IL-32) are analyzed. Most effective combinations of cytokines are investigated. MATERIAL & METHOD Antitumor activity against U373MG, U87MG were measured by co-culture with PBMC and by nude mouse subcutaneous transplantation model. Cytokine receptors on PBMC and glioma cell lines were examined by IHC and mRNA expression. Anti-tumor activity was measured by local injection and systemic administration of proinflammatory cytokines. Cell cycle alteration and expression of apoptosis-related genes after cytokine administration was analyzed. Serum concentraion of cytokines is measured by ELISA. RESULT Cytokine receptors were not expressed on glioma cells but were present on intratmoral mononuclear cells. Anti-tumor activity against transplanted tumor is strongly observed by focal administration. Expression of apoptosis-related genes were augmented. IFN-gamma was strongly induced by TNF-alpha, IL-2 and IL-12 administration. IFN-gamma, IL-17, TNF-alpha were also induced. IL-27 and IL-32 per se did not induce IFN-gamma. Simultaneous IL-27 and IL-12 induced strong IFN-gamma induction. Anti-glioma activity of IL-12 and IL-23 were higher than the same dose of exogenous IFN-gamma. IFN-gamma, IL-2 plus IL-12 in U373MG, and IFN-gamma, IL-2 plus IL-18 in U87MG seemed to be the best combination. CONCLUSIONS Strong anti-glioma activity was induced by proinflammatory cytokines at least partially through IFN-gamma. There may be another factors. IL-2 and IL-23 showed anti-tumor activity through IFN-gamma, IL-17, TNF-alpha. IFN-gamma + IL-2 + IL-12/-18 seems to be the best combination.