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ADAM17 regulates TNF? production by placental trophoblasts.

ABSTRACT: Increased trophoblast TNF? production is an important component of placental dysfunction in preeclampsia. However, the mechanism of increased TNF? production in the preeclamptic placenta is largely unknown. ADAM17 is a metallopeptidase that functions as a TNF? converting enzyme. In this study, we examined ADAM17 expression in placentas from normal and preeclamptic pregnancies and found increased ADAM17 expression in preeclamptic placentas compared to those from normal placentas, p < 0.05. Since hypoxia/oxidative stress is an underlying pathophysiology in the preeclamptic placenta, we further determined if hypoxia/oxidative stress could modulate ADAM17 expression and subsequently induce TNF? production in placental trophoblasts. Trophoblasts were isolated from normal term placentas and treated with cobalt (II) chloride (CoCl(2)), a hypoxia mimetic agent, at different concentrations. Our results showed that CoCl(2) induced a dose-dependent increase in TNF? production that is associated with enhanced ADAM17 expression. Trophoblast expressions of HO-1 (a sensor of cellular oxidative stress) and caspase-3 (an indicator of apoptosis) in response to CoCl(2) stimulation were also examined. We further found that metallopeptidase inhibitor GM6001 and ADAM17 siRNA could block CoCl(2) induced TNF? production, demonstrating the role of ADAM17 in TNF? production in placental trophoblasts. These results suggest that oxidative stress-induced increased ADAM17 expression could contribute to the increased TNF? production in preeclamptic placentas.

SUBMITTER: Ma R

PROVIDER: S-EPMC3360543 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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ADAM17 regulates TNFα production by placental trophoblasts.

Ma R R Gu Y Y Groome L J LJ Wang Y Y

Placenta 20111020 12

Increased trophoblast TNFα production is an important component of placental dysfunction in preeclampsia. However, the mechanism of increased TNFα production in the preeclamptic placenta is largely unknown. ADAM17 is a metallopeptidase that functions as a TNFα converting enzyme. In this study, we examined ADAM17 expression in placentas from normal and preeclamptic pregnancies and found increased ADAM17 expression in preeclamptic placentas compared to those from normal placentas, p < 0.05. Since ...[more]

PMID: 22018416

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Project description:Hepatitis B virus (HBV) infection is a global epidemic. The main transmission route of chronic HBV infection is from mother to child, yet the mechanisms underlying HBV intrauterine infection remain unclear. In the present study, the effect and the mechanism underlying hepatitis B virus X antigen (HBxAg) on HBV replication and EGFR activation in trophoblasts was investigated. Serum samples from pregnant women with HBV infection were used to infect trophoblasts and HBxAg expression was detected using ELISA. HBV plasmids carrying either full length hepatitis B virus X (HBx) or HBx with a deletion mutation (ΔHBx) were transfected into trophoblasts and expression levels of HBV DNA, hepatitis B e-antigen and pregenomic (pg)RNA, and structural maintenance of chromosomes (Smc) 5/6 were assessed. The association between HBx and EGFR promoters was characterized using a luciferase reporter assay and EGFR/PI3K/phosphorylated (p)-AKT expression and apoptosis rate were also monitored. The results of the present study indicated that HBxAg expression increased with the increasing titre of HBV DNA (P<0.05). Compared with the wild-type group, the amount of HBV DNA in the supernatant and cells was significantly reduced (P<0.05) in the ΔHBx group and the intracellular HBeAg and pgRNA levels were also significantly decreased (P<0.05). In addition, Smc5/6 expression was also significantly decreased (P<0.05) when the intracellular HBx protein was expressed compared with mock-transfected cells. Co-transfection of HBx and EGFR promoter plasmids in JEG-3 and HTR-8 cells significantly elevated EGFR promoter driven luciferase expression relative to the control group (P<0.01). In EGFR overexpressing cells, the expression of PI3K/p-AKT was significantly increased, whereas the apoptosis rate was significantly decreased (P<0.05). These results were reversed in the EGFR-knockdown group. In conclusion, the present study demonstrated that HBx promotes HBV replication in trophoblasts via downregulation of Smc5/6, activates the EGFR promoter and inhibits trophoblast apoptosis via the PI3K/p-AKT downstream signalling pathway, thereby increasing the risk of HBV intrauterine infection.

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ADAM17 regulates TNF? production by placental trophoblasts.

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ADAM17 regulates TNFα production by placental trophoblasts.

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