Molecular mechanisms of the induction of IL-12 and its inhibition by IL-10.
Molecular mechanisms of the induction of IL-12 and its inhibition by IL-10.
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DOI：
10.4049/jimmunol.160.12.5936
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发表时间：
1998-06
影响因子：
4.4
通讯作者：
M. Aste‐Amezaga;Xiaojing Ma;A. Sartori;G. Trinchieri
中科院分区：
文献类型：
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作者：
M. Aste‐Amezaga;Xiaojing Ma;A. Sartori;G. Trinchieri
外源性添加的白细胞介素 - 10（IL - 10）可迅速抑制金黄色葡萄球菌或脂多糖（LPS）诱导的人外周血单个核细胞（PBMCs）和单核细胞中细胞因子mRNA的表达，在诱导剂添加前20小时至添加后1小时添加IL - 10时观察到最大效应。核连缀分析显示，对白细胞介素 - 12 p40、白细胞介素 - 12 p35和肿瘤坏死因子 - α（TNF - α）的抑制作用发生在基因转录水平，并且向金黄色葡萄球菌或LPS处理的PBMCs中添加IL - 10不影响mRNA的稳定性。白细胞介素 - 10的抑制活性可被放线菌酮（CHX）消除，这表明有新合成的蛋白质参与。在金黄色葡萄球菌或LPS之前2小时添加CHX也抑制白细胞介素 - 12 p40 mRNA的积累，但不抑制白细胞介素 - 12 p35和TNF - α mRNA。这一发现表明p40转录是通过一种新合成的蛋白质因子调节的，而在金黄色葡萄球菌激活后2小时添加CHX会导致白细胞介素 - 12 p40、白细胞介素 - 12 p35和TNF - α基因的超诱导。这些结果表明，在人单核细胞中，白细胞介素 - 10对白细胞介素 - 12 p40和白细胞介素 - 12 p35基因的抑制机制主要发生在转录水平，并且白细胞介素 - 12 p40和p35基因的诱导对新蛋白质合成有不同的要求。
Exogenously added IL-10 rapidly inhibited Staphylococcus aureus- or LPS-induced cytokine mRNA expression in human PBMCs and monocytes, with a maximal effect observed when IL-10 was added from 20 h before until 1 h after the addition of the inducers. Nuclear run-on assays revealed that the inhibition of IL-12 p40, IL-12 p35, and TNF-alpha was at the gene transcriptional level and that the addition of IL-10 to S. aureus- or LPS-treated PBMCs did not affect mRNA stability. The inhibitory activity of IL-10 was abrogated by cycloheximide (CHX), suggesting the involvement of a newly synthesized protein(s). The addition of CHX at 2 h before S. aureus or LPS also inhibited the accumulation of IL-12 p40 mRNA, but did not inhibit IL-12 p35 and TNF-alpha mRNA. This finding suggests that p40 transcription is regulated through a de novo synthesized protein factor(s), whereas the addition of CHX at 2 h after S. aureus activation caused superinduction of the IL-12 p40, IL-12 p35, and TNF-alpha genes. These results indicate that in human monocytes, the mechanism(s) of IL-10 suppression of both IL-12 p40 and IL-12 p35 genes is primarily seen at the transcriptional level, and that the induction of the IL-12 p40 and p35 genes have different requirements for de novo protein synthesis.