Regulation of the IL-23 and IL-12 balance by Stat3 signaling in the tumor microenvironment.
Regulation of the IL-23 and IL-12 balance by Stat3 signaling in the tumor microenvironment.
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DOI：
10.1016/j.ccr.2008.12.018
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发表时间：
2009-02-03
期刊：
影响因子：
50.3
通讯作者：
Yu H
中科院分区：
文献类型：
--
作者：
Kortylewski M;Xin H;Kujawski M;Lee H;Liu Y;Harris T;Drake C;Pardoll D;Yu H
肿瘤和免疫细胞之间的相互作用可以增强或抑制癌症进展。我们在这里表明，肿瘤微环境中的Stat 3信号诱导促癌细胞因子IL-23，同时抑制中枢抗癌细胞因子IL-12，从而将肿瘤免疫的平衡转向致癌作用。Stat 3通过IL-23/p19基因的直接转录激活诱导IL-23的表达，IL-23主要由肿瘤相关巨噬细胞产生。此外，Stat 3抑制肿瘤相关树突状细胞中NF-κB/c-Rel依赖性IL-12/p35基因的表达。肿瘤相关调节性T细胞（Treg）表达IL-23受体（IL-23 R），其激活该细胞类型中的Stat 3，导致Treg特异性转录因子Foxp 3和免疫抑制细胞因子IL-10的上调。这些结果表明，Stat 3促进IL-23介导的促癌免疫应答，同时抑制IL-12依赖性抗肿瘤免疫。最近的研究表明，两种相关的细胞因子，IL- 23和IL- 12，在肿瘤发生中起相反的作用。然而，调节肿瘤微环境中这些细胞因子之间平衡的潜在机制尚未阐明。IL-23促进肿瘤免疫逃避的机制还有待探索。我们的研究结果表明，肿瘤微环境中的Stat 3信号传导调节IL-12/IL-23平衡，并且IL- 23部分地通过IL-23受体依赖性Stat 3激活来增强肿瘤微环境中调节性T细胞的免疫抑制活性。由于Stat 3是癌症中通常激活的信号通路的汇聚点，我们的数据揭示了致癌通路调节免疫微环境以促进肿瘤发展的机制。
Interactions between tumor and immune cells either enhance or inhibit cancer progression. We show here that Stat3 signaling within the tumor microenvironment induces a pro-carcinogenic cytokine, IL-23, while inhibiting a central anti-carcinogenic cytokine, IL-12, thereby shifting the balance of tumor immunity towards carcinogenesis. Stat3 induces expression of IL-23, which is mainly produced by tumor-associated macrophages, via direct transcriptional activation of the IL-23/p19 gene. Furthermore, Stat3 inhibits NF-κB/c-Rel-dependent IL-12/p35 gene expression in tumor-associated dendritic cells. Tumor-associated regulatory T cells (Treg) express IL-23 receptor (IL-23R) which activates Stat3 in this cell type, leading to upregulation of the Treg-specific transcription factor, Foxp3, and the immunosuppressive cytokine, IL-10. These results demonstrate that Stat3 promotes IL-23-mediated pro-carcinogenic immune responses while inhibiting IL-12-dependent anti-tumor immunity. Recent studies suggest that two related cytokines, IL- 23 and IL- 12, play opposite roles in carcinogenesis. However, the underlying mechanisms regulating the balance between these cytokines in the tumor microenvironment have not been elucidated. Mechanisms by which IL-23 promotes tumor immune evasion also remain to be explored. Our results reveal that Stat3 signaling in the tumor microenvironment regulates the IL-12/IL-23 balance and further, that IL- 23 enhances the immunosuppressive activity of regulatory T cells within the tumor microenvironment, in part via IL-23 receptor dependent Stat3 activation. Because Stat3 is a point of convergence for signaling pathways commonly activated in cancer, our data reveal a mechanism by which oncogenic pathways regulate the immune microenvironment to promote tumor development.
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影响因子：
32.4
作者：
Oppmann, B;Lesley, R;Kastelein, RA
通讯作者：
Kastelein, RA
DOI：
10.1084/jem.20010938
发表时间：
2002-02-04
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Gerosa F;Baldani-Guerra B;Nisii C;Marchesini V;Carra G;Trinchieri G
通讯作者：
Trinchieri G
影响因子：
30.5
作者：
Dunn, GP;Bruce, AT;Schreiber, RD
通讯作者：
Schreiber, RD
影响因子：
64.8
作者：
Shankaran, V;Ikeda, H;Schreiber, RD
通讯作者：
Schreiber, RD
影响因子：
4.4
作者：
Ghilardi, N;Kljavin, N;de Sauvage, FJ
通讯作者：
de Sauvage, FJ