The role of specific histone deacetylase (HDAC) proteins in regulating the lipopolysaccharide (LPS)-induced inflammatory response and its underlying mechanisms are unclear. Here, HDAC2, a class I HDAC family protein, is essential for the LPS-triggered inflammatory response in macrophages. LPS stimulation increases HDAC2 expression in macrophages. Knockdown of HDAC2 decreases the expression of proinflammatory genes, such as IL-12, TNF-α and iNOS following stimulation with LPS. The adoptive transfer of HDAC2 knockdown macrophages attenuates the LPS-triggered innate inflammatory response in vivo, and these mice are less sensitive to endotoxin shock and Escherichia coli-induced sepsis. Mechanistically, the c-Jun protein is the main target of HDAC2-mediated LPS-induced production of proinflammatory cytokines. Moreover, HDAC2 knockdown increases the expression of c-Jun, which directly binds the promoters of proinflammatory genes and forms nuclear receptor corepressor complexes to inhibit the transcription of proinflammatory genes in macrophages. These effects are rescued by c-Jun expression. According to the chromatin immunoprecipitation analysis, HDAC2 also selectively suppresses c-Jun expression by directly binding to its promoter and modifying histone acetylation after LPS stimulation. Our findings define a new function and mechanism of the HDAC2/c-Jun signaling network that regulates the LPS-induced immune response in macrophages.

中文翻译：

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组蛋白脱乙酰基酶2对于LPS诱导的巨噬细胞炎症反应至关重要。

尚不清楚特定的组蛋白脱乙酰基酶（HDAC）蛋白在调节脂多糖（LPS）诱导的炎症反应中的作用及其潜在机制。在这里，HDAC2是I类HDAC家族蛋白，对于LPS触发的巨噬细胞炎症反应至关重要。LPS刺激可增加巨噬细胞中HDAC2的表达。敲低HDAC2会降低LPS刺激后促炎基因（如IL-12，TNF-α和iNOS）的表达。HDAC2敲低巨噬细胞的过继转移减弱了LPS触发的体内先天炎症反应，并且这些小鼠对内毒素休克和大肠杆菌诱导的败血症敏感性较低。从机理上讲，c-Jun蛋白是HDAC2介导的LPS诱导的促炎细胞因子产生的主要靶标。此外，HDAC2敲低可增加c-Jun的表达，而c-Jun可直接结合促炎基因的启动子并形成核受体共抑制复合物，从而抑制巨噬细胞中促炎基因的转录。这些作用通过c-Jun表达得以挽救。根据染色质免疫沉淀分析，HDAC2还通过直接与其启动子结合并在LPS刺激后修饰组蛋白乙酰化来选择性抑制c-Jun表达。我们的发现定义了HDAC2 / c-Jun信号网络的新功能和机制，该网络调节LPS诱导的巨噬细胞免疫反应。这些作用通过c-Jun表达得以挽救。根据染色质免疫沉淀分析，HDAC2还通过直接与其启动子结合并在LPS刺激后修饰组蛋白乙酰化来选择性抑制c-Jun表达。我们的发现定义了HDAC2 / c-Jun信号网络的新功能和机制，该网络调节LPS诱导的巨噬细胞免疫反应。这些作用通过c-Jun表达得以挽救。根据染色质免疫沉淀分析，HDAC2还通过直接与其启动子结合并在LPS刺激后修饰组蛋白乙酰化来选择性抑制c-Jun表达。我们的发现定义了HDAC2 / c-Jun信号网络的新功能和机制，该网络调节LPS诱导的巨噬细胞免疫反应。