Silencing of SOCS1 in macrophages suppresses tumor development by enhancing antitumor inflammation
Silencing of SOCS1 in macrophages suppresses tumor development by enhancing antitumor inflammation
复制标题
DOI：
10.1111/j.1349-7006.2009.01098.x
复制
发表时间：
2009-04-01
期刊：
影响因子：
5.7
通讯作者：
Yoshimura, Akihiko
中科院分区：
文献类型：
--
作者：
Hashimoto, Masayuki;Ayada, Toranoshin;Yoshimura, Akihiko
炎症已被证明有助于肿瘤发展和抗肿瘤免疫。然而，决定这些相反的效果的条件还没有得到很好的理解。细胞因子信号转导抑制因子1（SOCS 1）在炎症和肿瘤发生发展中起重要作用。据报道，树突状细胞中SOCS 1基因的沉默增强了抗肿瘤免疫，而除T和B细胞外的整个器官中的SOCS 1缺陷增强了炎症介导的结肠肿瘤的发展。为了确定哪些类型的细胞对于SOCS 1缺陷抑制肿瘤发展很重要，我们采用了条件性敲除策略。通过SOCS 1-flox/flox小鼠与LysM-cre小鼠杂交，在巨噬细胞和中性粒细胞中缺失SOCS 1基因。所得的条件性敲除（cKO）小鼠显示出对内毒素休克的增强的敏感性。SOCS 1-cKO小鼠在B16黑色素瘤移植后的存活时间比野生型小鼠长得多。在SOCS 1-cKO小鼠中，1，2-二甲基肼（DMH）加葡聚糖硫酸钠（DSS）诱导的结肠癌发生也减少。单核细胞SOCS 1缺陷增强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SOCS 1缺陷诱导的炎症增强了抗肿瘤免疫应答，而不是促进肿瘤的炎症。（Cancer Sci 2009; 100：730-736）
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. (Cancer Sci 2009; 100: 730-736)