The Direct Effect of IL-12 on Tumor Cells: IL-12 Acts Directly on Tumor Cells to Activate NF-κB and Enhance IFN-γ-Mediated STAT1 Phosphorylation

Abstract

IL-12 directly acts on T cells and NK cells to induce IFN-γ production. IFN-γ plays an important role in anti-tumor effect of IL-12. In spite of various functions of IL-12 on immunocytes, the direct effect of IL-12 on tumor cells has not been fully clarified. The present study investigated the direct effect of IL-12 on eight murine tumor cell lines in vitro. IL-12 did not directly up-regulate expression of MHC class I on tumor cells, but enhanced IFN-γ-induced up-regulation of MHC class I expression in MC-38, MCA102, MCA205 and MCA207 cells. IL-12 alone did not activate STAT1, but IL-12 enhanced IFN-γ-mediated STAT1 phosphorylation in MC-38, MCA102, MCA205, MCA207 and Colon-26-NL-17 cells, which expressed IL-12 receptor β1 mRNA. In the other side, Panc-02, B16-BL6 and 266-6 cells were not affected by IL-12, in which expression of IL-12 receptor β1 mRNA was not detected. Anti-IL-12 mAb inhibited the direct effect of IL-12 on MC-38 cells. Moreover, nuclear localization of NF-κB was observed after stimulation of IL-12 or IL-12 p40 in MC-38 and Colon-26-NL-17 cells, but not in Panc-02 cells. These findings suggest that IL-12 directly acts on tumor cells through IL-12 receptor β1 to activate NF-κB and enhance IFN-γ-mediated STAT1 phosphorylation.