Antiproliferative Activity of IL-27 on Melanoma

IL-27 is a member of the IL-6/IL-12 family and activates both STAT1 and STAT3 through its receptor, which consists of WSX-1 and gp130. We previously demonstrated that IL-27 has potent antitumor activities, which are mediated through CD8(+) T cells, NK cells, or its own antiangiogenic activity. In th...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2008-05, Vol.180 (10), p.6527-6535
Main Authors: Yoshimoto, Takayuki, Morishima, Noriko, Mizoguchi, Izuru, Shimizu, Motomu, Nagai, Hiroshi, Oniki, Shuntaro, Oka, Masahiro, Nishigori, Chikako, Mizuguchi, Junichiro
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Blotting, Western
Cell Line, Tumor
Cell Proliferation - drug effects
Flow Cytometry
Histocompatibility Antigens Class I - metabolism
Humans
Interferon Regulatory Factor-1 - biosynthesis
Interferon Regulatory Factors - biosynthesis
Interleukins - metabolism
Interleukins - pharmacology
Melanoma, Experimental - drug therapy
Mice
Receptors, Cytokine - genetics
Receptors, Cytokine - metabolism
Reverse Transcriptase Polymerase Chain Reaction
RNA, Small Interfering
Signal Transduction - drug effects
Signal Transduction - physiology
STAT1 Transcription Factor - metabolism
STAT3 Transcription Factor - metabolism
Transfection
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Summary:IL-27 is a member of the IL-6/IL-12 family and activates both STAT1 and STAT3 through its receptor, which consists of WSX-1 and gp130. We previously demonstrated that IL-27 has potent antitumor activities, which are mediated through CD8(+) T cells, NK cells, or its own antiangiogenic activity. In this study, we demonstrate that IL-27 also possesses a direct antiproliferative activity on melanoma. Although WSX-1 expression was hardly detected in parental mouse melanoma B16F10 cells, IL-27 activated STAT1 and STAT3 and up-regulated MHC class I in B16F10 transfectants expressing wild-type WSX-1. In contrast, IL-27 failed to activate STAT1 and up-regulate MHC class I in those expressing mutant WSX-1, in which the putative STAT1-binding Tyr-609 of the cytoplasmic region was replaced by Phe. IL-27 inhibited the tumor growth of transfectants expressing wild-type WSX-1 in a dose-dependent manner. IL-27 augmented the expression of IFN regulatory factor (IRF)-1 and IRF-8, which possess tumor suppressor activities, in B16F10 transfectants expressing wild-type WSX-1. Down-regulation of IRF-1 but not IRF-8 with small interfering RNA partially blocked the IL-27-induced growth inhibition. A small, but significant, direct antiproliferative effect of IL-27 was also observed in vivo. Moreover, several human melanoma cells were revealed to express both IL-27 receptor subunits, and activation of STAT1 and STAT3 and growth inhibition by IL-27 were detected. These results suggest that IL-27 has an antiproliferative activity on melanomas through WSX-1/STAT1 signaling. Thus, IL-27 may be an attractive candidate as an antitumor agent applicable to cancer immunotherapy.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.180.10.6527