The direct effect of IL-12 on tumor cells: IL-12 acts directly on tumor cells to activate NF-kappaB and enhance IFN-gamma-mediated STAT1 phosphorylation.
IL-12 directly acts on T cells and NK cells to induce IFN-gamma production. IFN-gamma 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-gamma-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-gamma-mediated STAT1 phosphorylation in MC-38, MCA102, MCA205, MCA207 and Colon-26-NL-17 cells, which expressed IL-12 receptor beta1 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 beta1 mRNA was not detected. Anti-IL-12 mAb inhibited the direct effect of IL-12 on MC-38 cells. Moreover, nuclear localization of NF-kappaB 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 beta1 to activate NF-kappaB and enhance IFN-gamma-mediated STAT1 phosphorylation.
Su
W
W
Department of Surgery (E1), Osaka University Graduate School of Medicine, Osaka, Japan.
Ito
T
T
Oyama
T
T
Kitagawa
T
T
Yamori
T
T
Fujiwara
H
H
Matsuda
H
H
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology*; D018664:Interleukin-12 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000276:immunology / Q000494:pharmacology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018123:Receptors, Interleukin / Q000378:metabolism; D053707:Receptors, Interleukin-12; D050794:STAT1 Transcription Factor; D050797:STAT4 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects
D000911:Antibodies, Monoclonal; D004268:DNA-Binding Proteins; D015395:Histocompatibility Antigens Class I; C508440:Il12rb1 protein, mouse; D016328:NF-kappa B; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D050794:STAT1 Transcription Factor; D050797:STAT4 Transcription Factor; C494080:Stat1 protein, mouse; C494091:Stat4 protein, mouse; D015534:Trans-Activators; D018664:Interleukin-12; D007371:Interferon-gamma; D004247:DNA