Systemic administration of IL-23 induces potent antitumor immunity primarily mediated through Th1-type response in association with the endogenously expressed IL-12.

Abstract

IL-23, a cytokine, which is composed of the p40 subunit shared with IL-12 and the IL-23-specific p19 subunit, has been shown to preferentially act on Th1 effector/memory CD4+ T cells and to induce their proliferation and IFN-gamma production. The IL-23 is also reported to act on Th17-CD4+ T cells, which are involved in inducing tissue injury. In this study, we examined the antitumor effects associated with systemic administration of IL-23 and their mechanisms in mouse tumor system. Systemic administration of high-dose IL-23 was achieved using in vivo electroporation of IL-23 plasmid DNA into the pretibial muscles of C57BL/6 mice. The IL-23 treatment was associated with significant suppression of the growth of pre-existing MCA205 fibrosarcoma and prolongation of the survival of treated mice without significant toxicity when compared with those of the mice treated with EGFP. Although the therapeutic outcomes were similar to those with the IL-12 treatment, the IL-23 treatment induced characteristic immune responses distinctive to those of IL-12 treatment. The IL-23 administration even at the therapeutic levels did not induce detectable IFN-gamma concentration in the serum. In vivo depletion of CD4+ T cells, CD8+ T cells, or NK cells significantly inhibited the antitumor effects of IL-23. Furthermore, the CD4+ T cells in the lymph nodes in the IL-23-treated mice showed significant IFN-gamma and IL-17 response upon anti-CD3 mAb stimulation in vitro. These results and the ones in the IFN-gamma or IL-12 gene knockout mice suggest that potent antitumor effects of IL-23 treatment could be achieved when the Th1-type response is fully promoted in the presence of endogenously expressed IL-12.

• Authors: Teruo Kaiga, Marimo Sato, Hide Kaneda, Yoichiro Iwakura, Tadatoshi Takayama, Hideaki Tahara
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 178 Issue 12 Pg. 7571-80 (Jun 15 2007) ISSN: 0022-1767 [Print] United States
• PMID: 17548592 (Publication Type: Journal Article)

Chemical References

• Interleukin-17
• Interleukin-23
• Interleukin-12
• Interferon-gamma

Topics

• Animals
• CD4-Positive T-Lymphocytes (immunology)
• CD8-Positive T-Lymphocytes (immunology)
• Cell Line, Tumor
• Interferon-gamma (blood, genetics, metabolism)
• Interleukin-12 (metabolism)
• Interleukin-17 (metabolism)
• Interleukin-23 (administration & dosage, genetics, metabolism)
• Killer Cells, Natural (immunology)
• Lymphocyte Activation
• Lymphocyte Depletion
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Neoplasm Transplantation
• Neoplasms (drug therapy, immunology)
• Th1 Cells (immunology)