Yoshimoto Takayuki, Morishima Noriko, Mizoguchi Izuru, Shimizu Motomu, Nagai Hiroshi, Oniki Shuntaro, Oka Masahiro, Nishigori Chikako, Mizuguchi Junichiro
Intractable Immune System Disease Research Center, Tokyo Medical University, Tokyo, Japan.
J Immunol. 2008 May 15;180(10):6527-35. doi: 10.4049/jimmunol.180.10.6527.
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.
白细胞介素-27（IL-27）是白细胞介素-6/白细胞介素-12家族的成员，通过其由WSX-1和gp130组成的受体激活信号转导和转录激活因子1（STAT1）和信号转导和转录激活因子3（STAT3）。我们之前证明IL-27具有强大的抗肿瘤活性，其通过CD8(+) T细胞、自然杀伤（NK）细胞或其自身的抗血管生成活性介导。在本研究中，我们证明IL-27对黑色素瘤也具有直接的抗增殖活性。尽管在亲本小鼠黑色素瘤B16F10细胞中几乎检测不到WSX-1的表达，但IL-27在表达野生型WSX-1的B16F10转染细胞中激活了STAT1和STAT3，并上调了主要组织相容性复合体I类（MHC I类）分子的表达。相反，IL-27在表达突变型WSX-1的细胞中未能激活STAT1，也未能上调MHC I类分子的表达，在突变型WSX-1中，胞质区域假定的与STAT1结合的酪氨酸609被苯丙氨酸取代。IL-27以剂量依赖性方式抑制表达野生型WSX-1的转染细胞的肿瘤生长。IL-27增强了表达野生型WSX-1的B16F10转染细胞中具有肿瘤抑制活性的干扰素调节因子（IRF）-1和IRF-8的表达。用小干扰RNA下调IRF-1而非IRF-8可部分阻断IL-27诱导的生长抑制。在体内也观察到IL-27有微小但显著的直接抗增殖作用。此外，发现几种人黑色素瘤细胞表达IL-27受体的两个亚基，并且检测到IL-27激活了STAT1和STAT3并抑制了细胞生长。这些结果表明，IL-27通过WSX-1/STAT1信号通路对黑色素瘤具有抗增殖活性。因此，IL-27可能作为一种适用于癌症免疫治疗的抗肿瘤药物是一个有吸引力的候选物。
