Hashimoto Masayuki, Ayada Toranoshin, Kinjyo Ichiko, Hiwatashi Kiyokazu, Yoshida Hideyuki, Okada Yasunori, Kobayashi Takashi, Yoshimura Akihiko
Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Cancer Sci. 2009 Apr;100(4):730-6. doi: 10.1111/j.1349-7006.2009.01098.x.
Inflammation has been shown to contribute to both tumor development and antitumor immunity. However, conditions determining these opposing effects are not well understood. Suppressor of cytokine signaling 1 (SOCS1) has been shown to play an important role in regulating inflammation and tumor development. It has been reported that silencing of SOCS1 gene in dendritic cells potentiates antitumor immunity, while SOCS1-deficiency in whole organs except for T and B cells enhances inflammation-mediated colon tumor development. To determine which types of cells are important for the suppression of tumor development by SOCS1-deficiency, we employed the conditional knockout strategy. SOCS1 gene was deleted in macrophages and neutrophils by crossing SOCS1-flox/flox mice with LysM-cre mice. Resulting conditional knockout (cKO) mice showed enhanced sensitivity to endotoxin shock. SOCS1-cKO mice survived much longer than wild-type mice after B16 melanoma transplantation. Colon carcinogenesis induced by 1,2-dimethylhydrazine (DMH) plus dextran sulfate sodium (DSS) was also reduced in SOCS1-cKO mice. SOCS1-deficiency in monocytic cells enhanced tumor-killing activity of macrophages and tumor-specific cytotoxic T cell activity. These results suggest that inflammation induced by SOCS1-deficiency in monocytes potentiates antitumor immune responses rather than tumor-promoting inflammation.
炎症已被证明与肿瘤发展和抗肿瘤免疫均有关联。然而，决定这些相反作用的条件尚未完全明确。细胞因子信号传导抑制因子1（SOCS1）已被证明在调节炎症和肿瘤发展中发挥重要作用。据报道，树突状细胞中SOCS1基因的沉默可增强抗肿瘤免疫，而除T细胞和B细胞外的全身器官中SOCS1的缺失则会促进炎症介导的结肠肿瘤发展。为了确定哪些细胞类型对于SOCS1缺失抑制肿瘤发展至关重要，我们采用了条件性敲除策略。通过将SOCS1-flox/flox小鼠与LysM-cre小鼠杂交，在巨噬细胞和中性粒细胞中删除SOCS1基因。产生的条件性敲除（cKO）小鼠对内毒素休克的敏感性增强。在移植B16黑色素瘤后，SOCS1-cKO小鼠的存活时间比野生型小鼠长得多。在SOCS1-cKO小鼠中，由1,2-二甲基肼（DMH）加葡聚糖硫酸钠（DSS）诱导的结肠癌发生也有所减少。单核细胞中SOCS1的缺失增强了巨噬细胞的肿瘤杀伤活性和肿瘤特异性细胞毒性T细胞活性。这些结果表明，单核细胞中SOCS1缺失诱导的炎症增强了抗肿瘤免疫反应，而非促进肿瘤的炎症。
