title: Coexpression of IL-18 strongly attenuates IL-12-induced systemic toxicity through a rapid induction of IL-10 without affecting its antitumor capacity.
abstract: 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-alpha and IFN-gamma. 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.
authors.affiliation: Laboratory of Experimental Immunology, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA. crodri@bioclin.fcq.unc.edu.ar
authors.forename: Maria Cecilia
authors.initials: MC
authors.lastname: Rodriguez-Galan
authors.forename: Della
authors.initials: D
authors.lastname: Reynolds
authors.forename: Silvia G
authors.initials: SG
authors.lastname: Correa
authors.forename: Pablo
authors.initials: P
authors.lastname: Iribarren
authors.forename: Morihiro
authors.initials: M
authors.lastname: Watanabe
authors.forename: Howard A
authors.initials: HA
authors.lastname: Young
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000378:metabolism* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D018076:DNA, Complementary / Q000008:administration & dosage / Q000096:biosynthesis; D004359:Drug Therapy, Combination; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000097:blood / Q000172:deficiency; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000172:deficiency / Q000627:therapeutic use*; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000097:blood / Q000627:therapeutic use / Q000633:toxicity*; D020382:Interleukin-18 / Q000096:biosynthesis* / Q000502:physiology / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000276:immunology / Q000401:mortality / Q000556:secondary / Q000628:therapy*; D008546:Melanoma, Experimental / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000097:blood
chemical_list: D000970:Antineoplastic Agents; D018076:DNA, Complementary; D020382:Interleukin-18; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma