CIBICI   14215
CENTRO DE INVESTIGACION EN BIOQUIMICA CLINICA E INMUNOLOGIA
Unidad Ejecutora - UE
artículos
Título:
Co-expression of IL-18 strongly attenuates IL-12-induced systemic toxicity through a rapid induction of IL-10 without affecting its anti-tumor capacity
Autor/es:
RODRIGUEZ-GALAN, M. C.; REYNOLDS, D; COREA, SG; IRIBARREN, P; WATANABE, M; YOUNG, HA
Revista:
JOURNAL OF IMMUNOLOGY
Referencias:
Año: 2009
ISSN:
0022-1767
Resumen:
body { background: #FFFFFF; margin: 0px; padding: 0px; } IL-12 is an excellent candidate for the treatment of cancer due to its ability to drive strong anti-tumor responses. Recombinant IL-12 protein is currently used in cancer patients; however, systemic expression of rIL-12 presents disadvantages including cost and dose limitation due to its toxicity. In this study we used hydrodynamic shear of cDNA as a tool to achieve systemic expression of IL-12. We found that sustained but toxic levels of serum IL-12 could be generated in 6-7 week old B6 mice after a single injection of the cDNA. Unexpectedly, we observed that when IL-12 cDNA is co-injected with IL-18 cDNA, IL-12 anti-tumor activity was maintained but there was a significant attenuation of IL-12 toxicity, as evidenced by a greater survival index and a diminution of liver enzymes (ALT and AST). Interestingly, after IL-12+IL-18 cDNA administration, more rapid and higher IL-10 levels were observed than after IL-12 cDNA treatment alone. To understand the mechanism of protection, we co-injected IL-12+IL-10 cDNAs and observed an increase in survival that correlated with diminished serum levels of the inflammatory cytokines TNFa and IFNg. Confirming the protective role of early IL-10 expression, we observed a significant decrease in survival in IL-10 KO mice or IL-10R-blocked B6 mice after IL-12+IL-18 treatment. Thus, our data demonstrate that the high and early IL-10 expression induced after IL-12+IL-18 cDNA treatment is critical to rapidly attenuate IL-12 toxicity without affecting its anti-tumor capacity. These data could highly contribute to the design of more efficient/less toxic protocols for the treatment of cancer.