Cui Bijun, Lu Shen, Lai Lihua, Xie Yiwei, He Jia, Xue Yue, Xiao Peng, Pan Ting, Chen Luoquan, Liu Yang, Cao Xuetao, Wang Qingqing
Institute of Immunology, Zhejiang University School of Medicine , Hangzhou, China.
Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China; National Key Laboratory of Medical Molecular Biology and Department of Immunology, Chinese Academy of Medical Sciences, Beijing, China.
Oncoimmunology. 2017 Jan 20;6(2):e1268309. doi: 10.1080/2162402X.2016.1268309. eCollection 2017.
Numerous studies have demonstrated that inflammation contributes to a variety of cancer formation, among them, colitis-associated cancer (CAC) represents a typical inflammation-related cancer. Interleukin 27 (IL-27) has been demonstrated to play an important role in inflammation-related disease. The effect of IL-27 in intestinal inflammation is controversial and its role in CAC is not elucidated yet. In our present study, we found that IL-27 has protective function in murine model of CAC through suppression of inflammatory cytokines in intestinal epithelial cells (IECs). IL-27Rα (WSX-1) deficiency promotes the CAC development in mice, which is driven by enhanced tumor cell proliferation, more intensive myeloid-derived suppressor cells (MDSC) accumulation in colon lamina propria and higher level of inflammatory cytokines and chemokines in IECs. The levels of IL-6, TNF-α, GM-CSF and CXCL1 triggered by toll-like receptor ligands are significantly upregulated in IECs from WSX-1 KO mice. Removal of commensal microorganism through antibiotic treatment in mice to eliminate TLR ligands deprives the protective function of IL-27 on CAC tumor growth. Thus, IL-27 suppresses CAC formation through an anti-inflammation mechanism targeting IECs and in turn resists the tumorigenesis. Hence, our study explained how IL-27 exerts its anti-inflammatory function on epithelial cells to fight against chronic-inflammation-associated cancer, which might provide new insights on the potential therapeutic strategies for cancer.
大量研究表明，炎症促成多种癌症的形成，其中，结肠炎相关癌（CAC）是一种典型的炎症相关癌症。白细胞介素27（IL-27）已被证明在炎症相关疾病中发挥重要作用。IL-27在肠道炎症中的作用存在争议，其在CAC中的作用尚未阐明。在我们目前的研究中，我们发现IL-27在CAC小鼠模型中具有保护作用，通过抑制肠道上皮细胞（IECs）中的炎性细胞因子来实现。IL-27Rα（WSX-1）缺陷会促进小鼠CAC的发展，这是由肿瘤细胞增殖增强、结肠固有层中髓源性抑制细胞（MDSC）更密集的积累以及IECs中更高水平的炎性细胞因子和趋化因子驱动的。在来自WSX-1基因敲除小鼠的IECs中，由Toll样受体配体触发的IL-6、TNF-α、GM-CSF和CXCL1水平显著上调。通过抗生素治疗去除小鼠体内的共生微生物以消除TLR配体，会剥夺IL-27对CAC肿瘤生长的保护作用。因此，IL-27通过靶向IECs的抗炎机制抑制CAC的形成，进而抵抗肿瘤发生。因此，我们的研究解释了IL-27如何在上皮细胞上发挥抗炎功能以对抗慢性炎症相关癌症，这可能为癌症的潜在治疗策略提供新的见解。
