Melatonin (5-methoxy-N-acetyltryptamine), a hormone produced in the pineal gland, has a variety of biological functions as an antioxidant, but a functional role of melatonin in the regulation of intestinal mucin (Muc) production during bacterial infection has yet to be described in detail. In this study, we investigate the effects of melatonin during Muc2 repression elicited by the Gram-negative bacterium V. vulnificus. Mucus-secreting human HT29-MTX cells were used to study the functional role of melatonin during Muc2 depletion induced by the recombinant protein (r) VvpM produced by V. vulnificus. The regulatory effects of melatonin coupling with melatonin receptor 2 (MT2) on the production of reactive oxygen species (ROS), the activation of PKCδ and ERK, and the hypermethylation of the Muc2 promoter as induced by rVvpM were examined. Experimental mouse models of V. vulnificus infection were used to study the role of melatonin and how it neutralizes the bacterial toxin activity related to Muc2 repression. Recombinant protein (r) VvpM significantly reduced the level of Muc2 in HT29-MTX cells. The repression of Muc2 induced by rVvpM was significantly restored upon a treatment with melatonin (1 μM), which had been inhibited by the knockdown of MT2 coupling with Gαq and the NADPH oxidase subunit p47 phox. Melatonin inhibited the ROS-mediated phosphorylation of PKCδ and ERK responsible for region-specific hypermethylation in the Muc2 promoter in rVvpM-treated HT29-MTX cells. In the mouse models of V. vulnificus infection, treatment with melatonin maintained the level of Muc2 expression in the intestine. In addition, the mutation of the VvpM gene from V. vulnificus exhibited an effect similar to that of melatonin. These results demonstrate that melatonin acting on MT2 inhibits the hypermethylation of the Muc2 promoter to restore the level of Muc2 production in intestinal epithelial cells infected with V. vulnificus.

中文翻译：

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褪黑素通过褪黑素受体2与Gαq偶联恢复了由V. vulmificus VvpM诱导的Muc2耗竭

褪黑激素（5-甲氧基-N-乙酰基色胺）是一种在松果体中产生的激素，具有多种生物学功能，可作为抗氧化剂，但褪黑素在细菌感染过程中调节肠道粘蛋白（Muc）产生的功能尚未发挥作用。详细说明。在这项研究中，我们调查了褪黑素在革兰氏阴性菌V. vulnificus引起的Muc2抑制过程中的作用。分泌粘液的人HT29-MTX细胞用于研究褪黑激素在由V. vulnificus产生的重组蛋白（r）VvpM诱导的Muc2耗竭过程中的功能。研究了褪黑激素与褪黑激素受体2（MT2）耦合对活性氧（ROS）产生，PKCδ和ERK活化以及rVvpM诱导的Muc2启动子超甲基化的调节作用。实验用V. vulnificus感染小鼠模型研究褪黑激素的作用及其中和与Muc2抑制有关的细菌毒素活性的方法。重组蛋白VvpM显着降低了HT29-MTX细胞中Muc2的水平。rVvpM诱导的Muc2的抑制在褪黑素（1μM）处理后得到了显着恢复，褪黑素已被MT2与Gαq和NADPH氧化酶亚基p47 phox偶联的敲低抑制。褪黑素抑制了rVvpM处理的HT29-MTX细胞中Muc2启动子中ROS介导的PKCδ和ERK的磷酸化，而PKCδ和ERK负责区域特异性的高甲基化。在V. vulnificus感染的小鼠模型中，用褪黑激素治疗可维持肠道中Muc2表达的水平。另外，来自V的VvpM基因的突变。创伤表现出类似于褪黑激素的作用。这些结果表明，褪黑素作用于MT2抑制了Muc2启动子的甲基化，从而恢复了被V. vulnificus感染的肠道上皮细胞中Muc2的产生水平。