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 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.
Yoshimoto
Takayuki
T
Intractable Immune System Disease Research Center, Tokyo Medical University, Tokyo, Japan. yoshimot@tokyo-med.ac.jp
Morishima
Noriko
N
Mizoguchi
Izuru
I
Shimizu
Motomu
M
Nagai
Hiroshi
H
Oniki
Shuntaro
S
Oka
Masahiro
M
Nishigori
Chikako
C
Mizuguchi
Junichiro
J
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000096:biosynthesis; D050835:Interferon Regulatory Factors / Q000096:biosynthesis; D007378:Interleukins / Q000378:metabolism / Q000494:pharmacology*; D008546:Melanoma, Experimental / Q000188:drug therapy*; D051379:Mice; D034741:RNA, Small Interfering; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism*; D018123:Receptors, Interleukin; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014162:Transfection; D000099185:Interferon Regulatory Factor-8
D015395:Histocompatibility Antigens Class I; D050856:Interferon Regulatory Factor-1; D050835:Interferon Regulatory Factors; D007378:Interleukins; D034741:RNA, Small Interfering; D018121:Receptors, Cytokine; D018123:Receptors, Interleukin; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D000099185:Interferon Regulatory Factor-8; C486767:Il27 protein, mouse; C484747:Il27ra protein, mouse; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse