Bidirectional modulation of TNF-α transcription via α- and β-adrenoceptors in cultured astrocytes from rat spinal cord
Bidirectional modulation of TNF-α transcription via α- and β-adrenoceptors in cultured astrocytes from rat spinal cord
复制标题
通过大鼠脊髓培养星形胶质细胞中的 α 和 β 肾上腺素受体双向调节 TNF-α 转录
DOI：
10.1016/j.bbrc.2020.05.011
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发表时间：
2020
影响因子：
3.1
通讯作者：
Otsuguro Ken-ichi
中科院分区：
文献类型：
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作者：
Morimoto Kohei;Kitano Taisuke;Eguchi Ryota;Otsuguro Ken-ichi
去甲肾上腺素（NA）通过β-肾上腺素受体（AR）抑制脑星形胶质细胞中TNF-α的产生。然而，β-AR的下游通路以及α-AR的参与仍然未知。本研究探讨了AR对培养的大鼠脊髓星形胶质细胞TNF-α mRNA水平的调节作用。NA、α1激动剂苯肾上腺素和β激动剂异丙肾上腺素降低了TNF-α mRNA水平，而α2激动剂右美托咪定则增加了TNF-α mRNA水平。异丙肾上腺素诱导的TNF-α mRNA降低伴随着ERK磷酸化的降低。腺苷酸环化酶激活剂和ERK抑制剂模仿这些效果。这些结果表明β-ARs对TNF-α的转录调控是通过cAMP途径介导的，随后是ERK途径的抑制。右美托咪定诱导的TNF-α mRNA增加伴随JNK和ERK磷酸化，这被JNK抑制剂阻断。LPS诱导的TNF-α mRNA水平升高伴随NF-κB核转位，苯乙哌啶可阻断这两种作用。NF-κB抑制剂可抑制LPS诱导的TNF-α mRNA水平的升高。提示α1-ARs通过抑制NF-κB核转位抑制LPS诱导的TNF-α mRNA水平的升高。总之，我们的研究表明，α-和β-AR都参与了星形胶质细胞中TNF-α的转录调控。
Noradrenaline (NA) suppresses TNF-α production via β-adrenoceptors (ARs) in brain astrocytes. However, the downstream pathways from β-ARs, and the involvement of α-ARs, remains unknown. In this study, we investigated the AR-mediated regulation of TNF-α mRNA levels in cultured astrocytes from rat spinal cord. NA, the α1-agonist phenylephrine, and the β-agonist isoproterenol decreased the TNF-α mRNA level, while the α2-agonist dexmedetomidine increased it. The isoproterenol-induced TNF-α mRNA decrease was accompanied by a decrease in ERK phosphorylation. An adenylyl cyclase activator and an ERK inhibitor mimicked these effects. These results indicate that the transcriptional regulation of TNF-α by β-ARs is mediated via cAMP pathways followed by the ERK pathway inhibition. The dexmedetomidine-induced TNF-α mRNA increase was accompanied by phosphorylation of JNK and ERK, which was blocked by a JNK inhibitor. Furthermore, the LPS-induced increase in the TNF-α mRNA level was accompanied by NF-κB nuclear translocation, and both these effects were blocked by phenylephrine. An NF-κB inhibitor suppressed the LPS-induced increase in the TNF-α mRNA level. These results suggest that α1-ARs suppress the LPS-induced increase in the TNF-α mRNA level via inhibition of NF-κB nuclear translocation. Taken together, our study reveals that both α- and β-ARs are involved in the transcriptional regulation of TNF-α in astrocytes.