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Melatonin inhibits apoptotic cell death induced by Vibrio vulnificus VvhA via melatonin receptor 2 coupling with NCF-1.

ABSTRACT: Melatonin, an endogenous hormone molecule, has a variety of biological functions, but a functional role of melatonin in the infection of Gram-negative bacterium Vibrio vulnificus has yet to be described. In this study, we investigated the molecular mechanism of melatonin in the apoptosis of human intestinal epithelial (HCT116) cells induced by the hemolysin (VvhA) produced by V. vulnificus. Melatonin (1??M) significantly inhibited apoptosis induced by the recombinant protein (r) VvhA, which had been inhibited by the knockdown of MT2. The rVvhA recruited caveolin-1, NCF-1, and Rac1 into lipid rafts to facilitate the production of ROS responsible for the phosphorylation of PKC and JNK. Interestingly, melatonin recruited NCF-1 into non-lipid rafts to prevent ROS production via MT2 coupling with G?q. Melatonin inhibited the JNK-mediated phosphorylation of c-Jun responsible for Bax expression, the release of mitochondrial cytochrome c, and caspase-3/-9 activation during its promotion of rVvhA-induced apoptotic cell death. In addition, melatonin inhibited JNK-mediated phosphorylation of Bcl-2 responsible for the release of Beclin-1 and Atg5 expression during its promotion of rVvhA-induced autophagic cell death. These results demonstrate that melatonin signaling via MT2 triggers recruitment of NCF-1 into non-lipid rafts to block ROS production and JNK-mediated apoptotic and autophagic cell deaths induced by rVvhA in intestinal epithelial cells.

SUBMITTER: Lee SJ

PROVIDER: S-EPMC5833450 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Melatonin inhibits apoptotic cell death induced by Vibrio vulnificus VvhA via melatonin receptor 2 coupling with NCF-1.

Lee Sei-Jung SJ Lee Hyun Jik HJ Jung Young Hyun YH Kim Jun Sung JS Choi Sang Ho SH Han Ho Jae HJ

Cell death & disease 20180119 2

Melatonin, an endogenous hormone molecule, has a variety of biological functions, but a functional role of melatonin in the infection of Gram-negative bacterium Vibrio vulnificus has yet to be described. In this study, we investigated the molecular mechanism of melatonin in the apoptosis of human intestinal epithelial (HCT116) cells induced by the hemolysin (VvhA) produced by V. vulnificus. Melatonin (1 μM) significantly inhibited apoptosis induced by the recombinant protein (r) VvhA, which had ...[more]

PMID: 29352110

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Project description:BACKGROUND: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. METHODS: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. RESULTS: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. CONCLUSIONS: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.

Dataset Information

Melatonin inhibits apoptotic cell death induced by Vibrio vulnificus VvhA via melatonin receptor 2 coupling with NCF-1.

Publications

Melatonin inhibits apoptotic cell death induced by Vibrio vulnificus VvhA via melatonin receptor 2 coupling with NCF-1.

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