p300 promotes differentiation of Th17 cells via positive regulation of the nuclear transcription factor RORγt in acute respiratory distress syndrome
p300 promotes differentiation of Th17 cells via positive regulation of the nuclear transcription factor RORγt in acute respiratory distress syndrome
复制标题
p300 通过对急性呼吸窘迫综合征中核转录因子 RORγt 的正向调节促进 Th17 细胞分化
DOI：
10.1016/j.imlet.2018.07.004
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发表时间：
2018-10-01
影响因子：
4.4
通讯作者：
Qi, Di
中科院分区：
文献类型：
--
作者：
Chen, Yan;Wang, Daoxin;Qi, Di
急性呼吸窘迫综合征（ARDS）是危重患者急性呼吸衰竭的主要原因，也是全球数十年来死亡的主要原因之一。Th 17细胞参与了ARDS的发生和发展。此外，组蛋白乙酰转移酶（HAT）p300是一种转录辅激活因子，其活性与癌症和炎症性疾病密切相关。p300和组蛋白去乙酰化酶1（HDAC 1）与核转录因子视黄酸相关孤儿受体γ t（ROR γ t）相互作用并使其稳定，并通过乙酰化和去乙酰化参与调节辅助性T细胞17（Th 17）分化中ROR γ t介导的IL-17转录。然而，p300对ROR γ t和Th 17细胞在ARDS中的作用还没有很好的报道。因此，我们的目的是研究p300的临床特征及其对ROR γ t和Th 17细胞在ARDS患者以及脂多糖诱导的急性肺损伤（ALI）小鼠模型。p300和ROR γ t mRNA在ARDS患者外周血单个核细胞中的表达明显高于正常对照组（P < 0.05），其中以死亡者的表达最为显著（P < 0.05）。FOXP 3 mRNA水平下降与生存率相关，ROR γ t mRNA水平升高与感染相关（P < 0.05）。免疫组化分析显示p300和ROR γ t在ALI小鼠肺组织中的高表达。抑制剂介导的p300基因敲除可降低肺组织炎症和肺损伤评分（P < 0.05）。Western blotting和ELISA结果显示，p300抑制剂可使ALI小鼠肺组织ROR γ t的mRNA和蛋白水平以及白细胞介素17（IL-17）的产生减少（P < 0.05）。因此，我们的研究结果表明，p300可能发挥关键作用，在ARDS中积极调节ROR γ t转录，是一个潜在的新的免疫治疗ARDS的目标。
Acute respiratory distress syndrome (ARDS) has been the major cause of acute respiratory failure in critical patients and one of the leading causes of death worldwide for several decades. Th17 cells are involved in the occurrence and progression of ARDS. Furthermore, histone acetyltransferase (HAT) p300 is a transcriptional coactivator, and its activity is closely related to cancer and inflammatory diseases. p300 and histone deacetylase 1 (HDAC1) interact with and stabilize the nuclear transcription factor retinoic acid-related orphan receptor gamma t (ROR gamma t) and participate in the regulation of ROR gamma t-mediated IL-17 transcription in T helper 17 (Th17) cell differentiation by acetylation and deacetylation. However, the effect of p300 on ROR gamma t and Th17 cells in ARDS is not well reported. Therefore, we aimed to investigate the clinical features of p300 and its effect on ROR gamma t and Th17 cells in patients with ARDS as well as in lipopolysaccharide-induced acute lung injury (ALI) mouse models. Overexpression of p300 and ROR gamma t mRNA was found in the peripheral blood mononuclear cells from patients with ARDS, especially among non-survivors, compared to that in healthy individuals (P < 0.05). Moreover, the decline of FOXP3 mRNA level correlated with survival and increased ROR gamma t mRNA levels corelated with infection (P < 0.05). Immunohistochemical analysis revealed high p300 and ROR gamma t expression in ALI mouse lung tissues. Inhibitor-mediated knockdown of p300 reduced lung tissue inflammation and lung injury score (P < 0.05). Western blotting and ELISA revealed that p300 inhibitor caused a decrease in the mRNA and protein levels of ROR gamma t as well as interleukin 17 (IL-17) production in ALI mouse lung tissues (P < 0.05). Thus, our findings suggest that p300 may play a key role in ARDS by positively regulating ROR gamma t transcription and is a potential new immunotherapy target for ARDS.