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Coexpression of IL-18 Strongly Attenuates IL-12-Induced Systemic Toxicity through a Rapid Induction of IL-10 without Affecting its Antitumor Capacity¹

Maria Cecilia Rodriguez-Galan^2,*, Della Reynolds^*, Silvia G. Correa, Pablo Iribarren, Morihiro Watanabe^* and Howard A. Young^*

^* Laboratory of Experimental Immunology, Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702; and Inmunología. Centro de Investígaciones en Bioquímica Clínica e Inmunología and Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina

IL-12 is an excellent candidate for the treatment of cancer due to its ability to drive strong antitumor 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- to 7-wk-old B6 mice after a single injection of the cDNA. Unexpectedly, we observed that when IL-12 cDNA is coinjected with IL-18 cDNA, IL-12 antitumor 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 plus 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 coinjected IL-12 plus IL-10 cDNAs and observed an increase in survival that correlated with diminished serum levels of the inflammatory cytokines TNF- and IFN-. Confirming the protective role of early IL-10 expression, we observed a significant decrease in survival in IL-10 knockout mice or IL-10R-blocked B6 mice after IL-12 plus IL-18 treatment. Thus, our data demonstrate that the high and early IL-10 expression induced after IL-12 plus IL-18 cDNA treatment is critical to rapidly attenuate IL-12 toxicity without affecting its antitumor capacity. These data could highly contribute to the design of more efficient/less toxic protocols for the treatment of cancer.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This project has been funded with federal funds from the National Cancer Institute, National Institute of Health under Contract No. N01-CO-12400.

² Address correspondence and reprint requests to Maria Cecilia Rodriguez-Galan, Inmunología. CIBICI-CONICET, Haya de la Torre y Medina Allende. Facultad de Ciencias Químicas. Universidad Nacional de Córdoba. Argentina. E-mail address: crodri{at}bioclin.fcq.unc.edu.ar

³ Abbreviations used in this paper: KO, knockout; M, macrophage.