Natural killer cell is a major producer of interferon γ that is critical for the IL-12-induced anti-tumor effect in mice
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Although the anti-tumor effect of IL-12 is mediated mostly by IFNγ, which cell types most efficiently produce IFNγ and therefore initiate or promote the anti-tumor effect of IL-12 has not been clearly determined. In the present study, we demonstrated hydrodynamic injection of the IL-12 gene led to prolonged IFNγ production, NK-cell activation and complete inhibition of liver metastasis of CT-26 colon cancer cells in wild-type mice, but not in IFNγ knockout mice. NK cells expressed higher levels of STAT4 and upon IL-12 administration displayed stronger STAT4 phosphorylation and IFNγ production than non-NK cells. Adoptive transfer of wild-type NK cells into IFNγ knockout mice restored IL-12-induced IFNγ production, NK-cell activation and anti-tumor effect, whereas transfer of the same number of wild-type non-NK cells did not. In conclusion, NK cells are predominant producers of IFNγ that is critical for IL-12 anti-tumor therapy.
KeywordsIFNγ Innate immunity Liver tumor IL-12 NK
We thank Dr. Morihiro Watanabe (Laboratory of Experimental Immunology, Division of Basic Sciences, National Cancer Institute-Frederick Cancer Research and Development Center) for providing the pCMV-IL-12 plasmid, Dr. Yoichiro Iwakura (University of Tokyo, Institute of Medical Science) for providing GKO mice.
- 1.Kobayashi M, Fitz L, Ryan M, Hewick RM, Clark SC, Chan S, Loudon R, Sherman F, Perussia B, Trinchieri G (1989) Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J Exp Med 170(3):827–845CrossRefPubMedGoogle Scholar
- 2.Stern AS, Podlaski FJ, Hulmes JD, Pan YC, Quinn PM, Wolitzky AG, Familletti PC, Stremlo DL, Truitt T, Chizzonite R, Gately MK (1990) Purification to homogeneity and partial characterization of cytotoxic lymphocyte maturation factor from human B-lymphoblastoid cells. Proc Natl Acad Sci USA 87(17):6808–6812CrossRefPubMedGoogle Scholar
- 20.Watanabe M, Fenton RG, Wigginton JM, McCormick KL, Volker KM, Fogler WE, Roessler PG, Wiltrout RH (1999) Intradermal delivery of IL-12 naked DNA induces systemic NK cell activation and Th1 response in vivo that is independent of endogenous IL-12 production. J Immunol 163(4):1943–1950PubMedGoogle Scholar
- 34.Biber JL, Jabbour S, Parihar R, Dierksheide J, Hu Y, Baumann H, Bouchard P, Caligiuri MA, Carson W (2002) Administration of two macrophage-derived interferon-gamma-inducing factors (IL-12 and IL-15) induces a lethal systemic inflammatory response in mice that is dependent on natural killer cells but does not require interferon-gamma. Cell Immunol 216(1–2):31–42CrossRefPubMedGoogle Scholar
- 35.Tsushima H, Ito N, Tamura S, Matsuda Y, Inada M, Yabuuchi I, Imai Y, Nagashima R, Misawa H, Takeda H, Matsuzawa Y, Kawata S (2001) Circulating transforming growth factor beta 1 as a predictor of liver metastasis after resection in colorectal cancer. Clin Cancer Res 7(5):1258–1262PubMedGoogle Scholar
- 38.Galizia G, Lieto E, De Vita F, Romano C, Orditura M, Castellano P, Imperatore V, Infusino S, Catalano G, Pignatelli C (2002) Circulating levels of interleukin-10 and interleukin-6 in gastric and colon cancer patients before and after surgery: relationship with radicality and outcome. J Interferon Cytokine Res 22(4):473–482CrossRefPubMedGoogle Scholar
- 42.Sangro B, Mazzolini G, Ruiz J, Herraiz M, Quiroga J, Herrero I, Benito A, Larrache J, Pueyo J, Subtil JC, Olague C, Sola J et al (2004) Phase I trial of intratumoral injection of an adenovirus encoding interleukin-12 for advanced digestive tumors. J Clin Oncol 22(8):1389–1397CrossRefPubMedGoogle Scholar