Exogenous soluble VEGF receptor-1 (sFlt-1) regulates Th1/Th2 cytokine production from normal placental explants via intracellular calcium

Bei Xu, Charlene Thornton, Jane Tooher, Annemarie Hennessy
Hypertension in Pregnancy 2009, 28 (4): 448-56

OBJECTIVE: The increase of soluble VEGF-Receptor 1 (sFlt-1) is thought to contribute to the pathogenesis of preeclampsia. Soluble VEGF-Receptor 1 binds to circulating free VEGF and PLGF and this cascade is associated with endothelial dysfunction, a prominent feature of preeclampsia. Preeclampsia is also associated with excessive maternal response to pro-inflammatory stimuli manifesting as an imbalance of Th1/Th2 cytokine production at the maternal-fetal interface. Whether increased sFlt-1 expression has any effect on placental production of Th1/Th2 cytokines IL-10 and TNF-alpha is yet to be investigated. The aim of this study is to examine if exogenous sFlt-1 can regulate Th1/Th2 cytokines IL-10 and TNF-alpha production from normal placental explants via intracellular calcium release.

METHODS: Placental explants were taken from the decidual surface of normal non-laboured term placentas (n = 11).Villous explants were cultured with increasing concentrations of sFlt-1. The dose effect of sFlt-1 on placental Th1 and Th2 cytokine production (TNF-alpha and IL-10) were examined. Free PLGF, VEGF and sFlt-1 concentrations in the conditioned medium were also measured. Intracellular calcium blocker, 1,2-bis-(o-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid, tetra(acetoxymethyl)-ester (BAPTA/AM) was applied to investigate whether the changes in cytokine concentration were mediated by intracellular free calcium.

RESULTS: Placental IL-10 and TNF-alpha production were significantly increased after sFlt-1 incubation. The increase in IL-10 can be inhibited by BAPTA/AM. Soluble Flt-1 and free PLGF concentration in the conditioned medium was not changed. Free VEGF concentration in the conditioned medium was not detectable.

CONCLUSION: Exogenous sFlt-1 can increase TNF-alpha and IL-10 production from normal placental explants. The change in Th1/Th2 cytokine level may be mediated by intracellular free calcium.

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