Loss of TRIM24 promotes IL-10 expression via CBP/p300-dependent IFNβ1 transcription during macrophage activation
Loss of TRIM24 promotes IL-10 expression via CBP/p300-dependent IFNβ1 transcription during macrophage activation
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DOI：
10.1007/s00011-023-01751-x
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发表时间：
2023-06
影响因子：
6.7
通讯作者：
Zhaoyuan Hui;Yuanzheng Fu;Yun-Zhao Chen;J. Yin;H. Fang;Yifan Tu;Y. Gu;Jiawei Zhang
中科院分区：
文献类型：
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作者：
Zhaoyuan Hui;Yuanzheng Fu;Yun-Zhao Chen;J. Yin;H. Fang;Yifan Tu;Y. Gu;Jiawei Zhang
背景白细胞介素10（IL-10）作为一种抗炎细胞因子，在预防炎症和自身免疫性疾病以及维持免疫稳态方面发挥着重要作用。巨噬细胞中IL-10的产生受到多种途径的严格调节。TRIM 24是转录中间因子1（TIF 1）家族的成员，有助于抗病毒免疫和巨噬细胞M2极化。然而，TRIM 24在调节IL-10表达及其参与内毒素shocks.MethodsIn体外，骨髓来源的巨噬细胞与GM-CSF或M-CSF培养用LPS（100 ng/ml）刺激的作用仍不清楚。用不同剂量的内毒素（LPS）腹腔注射建立内毒素休克小鼠模型。采用RTPCR、RNA测序、ELISA及苏木精-伊红染色等方法，研究TRIM 24在内毒素休克中的作用及机制。TRIM 24的缺失在巨噬细胞中的LPS刺激的晚期期间促进IL-10表达。RNA-seq分析揭示了TRIM 24敲除巨噬细胞中IL-10的上游调节因子IFNβ1的上调。用CBP/p300抑制剂C646处理，减少了TRIM 24敲除和对照巨噬细胞之间IFNβ1和IL-10表达的差异。结论抑制TRIM 24可促进巨噬细胞活化过程中IFNβ1和IL-10的表达，从而保护小鼠免受内毒素休克。这项研究为TRIM 24在IL-10表达中的调节作用提供了新的见解，使其成为炎症性疾病的潜在有吸引力的治疗靶点。
BackgroundAs an anti-inflammatory cytokine, interleukin 10 (IL-10) plays a vital role in preventing inflammatory and autoimmune pathologies while also maintaining immune homeostasis. IL-10 production in macrophages is tightly regulated by multiple pathways. TRIM24, a member of the Transcriptional Intermediary Factor 1 (TIF1) family, contributes to antiviral immunity and macrophage M2 polarization. However, the role of TRIM24 in regulating IL-10 expression and its involvement in endotoxic shock remains unclear.MethodsIn vitro, bone marrow derived macrophages cultured with GM-CSF or M-CSF were stimulated with LPS (100ng/ml). Murine models of endotoxic shock were established by challenging the mice with different dose of LPS (i.p). RTPCR, RNA sequencing, ELISA and hematoxylin and eosin staining were performed to elucidate the role and mechanisms of TRIM24 in endotoxic shock.ResultsThe expression of TRIM24 is downregulated in LPS-stimulated bone marrow-derived macrophages (BMDMs). Loss of TRIM24 boosted IL-10 expression during the late stage of LPS-stimulation in macrophages. RNA-seq analysis revealed the upregulation of IFNβ1, an upstream regulator of IL-10, in TRIM24 knockout macrophages. Treatment with C646, a CBP/p300 inhibitor, diminished the difference in both IFNβ1 and IL-10 expression between TRIM24 knockout and control macrophages. Loss of TRIM24 provided protection against LPS-induced endotoxic shock in mice.ConclusionOur results demonstrated that inhibiting TRIM24 promoted the expression of IFNβ1 and IL-10 during macrophage activation, therefore protecting mice from endotoxic shock. This study offers novel insights into the regulatory role of TRIM24 in IL-10 expression, making it a potentially attractive therapeutic target for inflammatory diseases.