Molecular mechanism of lipopolysaccharide-induced SOCS-3 gene expression in macrophages and microglial
Molecular mechanism of lipopolysaccharide-induced SOCS-3 gene expression in macrophages and microglial
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DOI：
10.4049/jimmunol.179.9.5966
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发表时间：
2007-11-01
影响因子：
4.4
通讯作者：
Benveniste, Etty N.
中科院分区：
文献类型：
--
作者：
Qin, Hongwei;Roberts, Kevin L.;Benveniste, Etty N.
CNS内巨噬细胞/小胶质细胞的免疫活化导致细胞因子和趋化因子的产生，最终影响胶质细胞和神经元功能。细胞因子信号转导抑制因子（SOCS）蛋白是获得性免疫和先天性免疫应答的负性调节因子。我们以前的研究表明，SOCS-3在体外减弱巨噬细胞/小胶质细胞的活化，这表明SOCS-3可能在体内对免疫介导的CNS疾病发挥有益作用。在这项研究中，我们将LPS描述为巨噬细胞/小胶质细胞中SOCS-3转录和表达的有效诱导剂。对SOCS-3启动子的分析表明AP-1和IFN-γ激活序列（GAS）元件参与LPS诱导的SOCS-3转录。在稍后的时间点，IL-10缺陷型巨噬细胞中LPS诱导的SOCS-3表达减少，表明内源性IL-10参与了这种反应。使用STAT-3小干扰RNA阻断STAT-3表达和活化可降低LPS诱导的SOCS-3基因表达。LPS激活MAPK-ERK 1/2、JNK和p38通路，这些通路除了STAT-3外，还参与LPS诱导的SOCS-3表达。LPS处理细胞导致SOCS-3启动子上组蛋白H3和H4的乙酰化，STAT-3、c-Jun、c-Fos、CREB结合蛋白、p300和RNA聚合酶11以时间依赖性方式募集到内源性SOCS-3启动子。这些结果表明，LPS诱导的MAPK活化、内源性IL-10的产生和STAT-3活化在SOCS-3表达中起关键作用，SOCS-3表达提供了巨噬细胞和小神经胶质细胞中烟碱诱导的免疫和炎症反应的反馈衰减。
Immunological activation of macrophages/microglia within the CNS leads to the production of cytokines and chemokines that ultimately impact on glial and neuronal function. Suppressor of cytokine signaling (SOCS) proteins are negative regulators of adaptive and innate immune responses. Our previous studies demonstrated that SOCS-3 attenuates macrophage/microglial activation in vitro, suggesting that SOCS-3 may exert beneficial effects for immune-mediated CNS diseases in vivo. In this study, we describe LPS as a potent inducer of SOCS-3 transcription and expression in macrophages/microglia. An analysis of the SOCS-3 promoter indicates that AP-1 and IFN-gamma activation sequence (GAS) elements are involved in LPS-induced SOCS-3 transcription. LPS-induced SOCS-3 expression was diminished in IL-10-deficient macrophages at later time points, indicating the involvement of endogenous IL-10 in this response. Blocking STAT-3 expression and activation using STAT-3 small interfering RNA reduced LPS-induced SOCS-3 gene expression. LPS activated the MAPK-ERK1/2, JNK, and p38 pathways that, in addition to STAT-3, were also involved in LPS-induced SOCS-3 expression. LPS treatment of cells led to the acetylation of histones H3 and H4 on the SOCS-3 promoter and the recruitment of STAT-3, c-Jun, c-Fos, CREB-binding protein, p300, and RNA polymerase 11 to the endogenous SOCS-3 promoter in a time-dependent manner. These results indicate that LPS-induced MAPK activation, the production of endogenous IL-10, and STAT-3 activation play critical roles in SOCS-3 expression, which provides for feedback attenuation of cytokine-induced immune and inflammatory responses in macrophages and microglia.