Suppressors of cytokine signaling (SOCS)-1 and SOCS-3 are induced by CpG-DNA and modulate cytokine responses in APCs
Suppressors of cytokine signaling (SOCS)-1 and SOCS-3 are induced by CpG-DNA and modulate cytokine responses in APCs
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DOI：
10.4049/jimmunol.166.12.7082
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发表时间：
2001-06-15
影响因子：
4.4
通讯作者：
Heeg, K
中科院分区：
文献类型：
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作者：
Dalpke, AH;Opper, S;Heeg, K
在感染期间，先天免疫系统的功能状态受到严格调控。虽然导致激活的信号已经被很好地描述，但反调节机制却知之甚少。细胞因子信号转导抑制因子(SOCS)蛋白被认为是细胞因子诱导的造血细胞Janus激酶/STAT信号的负调节因子。为了分析病原体来源的刺激是否也能诱导SOCS蛋白，我们研究了CpG-DNA对巨噬细胞系、骨髓源性树突状细胞和腹膜巨噬细胞的诱导作用。在本研究中，我们发现CpG-DNA，而不是GPC-DNA，在体外和体内都能诱导SOCS-1和SOCS-3的mRNA表达。氯喹可阻断SOCS基因的表达，且不依赖于蛋白质合成。由CpG-DNA触发的丝裂原活化蛋白激酶通路的抑制剂能够阻止SOCS mRNA的诱导。CpG-DNA触发了SoCS蛋白的合成，可以通过Western blotting检测到。SOCS蛋白具有功能性，因为它们抑制了干扰素-γ以及IL-6和GM-CSF诱导的STAT蛋白的磷酸化。此外，干扰素-γ诱导的MHC-II类分子表达上调也被阻止。过表达SOCS-1也能达到同样的效果。因此，结果表明细胞内信号通路之间存在实质性的串扰。它们为Janus激酶/STAT信号在触发Toll样受体信号通路后的调节机制提供了证据。
During infection, the functional status of the innate immune system is tightly regulated. Although signals resulting in activation have been well characterized, counterregulative mechanisms are poorly understood. Suppressor of cytokine signaling (SOCS) proteins have been characterized as cytokine-inducible negative regulators of Janus kinase/STAT signaling in cells of hemopoietic origin. To analyze whether SOCS proteins could also be induced by pathogen-derived stimuli, we investigated the induction of SOCS-1 and SOCS-3 after triggering of macrophage cell lines, bone marrow-derived dendritic cells, and peritoneal macrophages with CpG-DNA. In this study, we show that CpG-DNA, but not GpC-DNA, induces expression of mRNA for SOCS-1 and SOCS-3 in vitro and in vivo. SOCS mRNA expression could be blocked by chloroquine and was independent of protein synthesis. Inhibitors of the mitogen-activated protein kinase pathway triggered by CpG-DNA were able to impede induction of SOCS mRNA. CpG-DNA triggered synthesis of SOCS proteins that could be detected by Western blotting. SOCS proteins were functional because they inhibited IFN-gamma as well as IL-6- and GM-CSF-induced phosphorylation of STAT proteins. Furthermore, IFN-gamma -induced up-regulation of MHC class II molecules was also prevented. The same effects could be achieved by overexpression of SOCS-1. Hence, the results indicate a substantial cross-talk between signal pathways within cells. They provide evidence for regulative mechanisms of Janus kinase/STAT signaling after triggering Toll-like receptor signal pathways.