Interleukin-6 stimulates placental lactogen expression by human trophoblast cells

Interleukin-6 (IL-6) stimulates the release of hCG from syncytiotrophoblast cells, but the effects of IL-6 and other cytokines on the release of placental lactogen (hPL) are unknown. To determine the effect of IL-6 on hPL release, we exposed an enriched fraction of trophoblast cells (prepared by the isopycnic centrifugation of enzymatically dispersed term placenta) continuously to IL-6 (500 U/ml) for up to 6 days. The amounts of hPL released by the IL-6-exposed cells during days 3 and 6 were 177.6 +/- 2.4% and 267.5 +/- 12.6% that of control cells, respectively (P < 0.0001 in each instance). In addition, the hPL messenger RNA (mRNA) contents of the IL-6-exposed cells after 3 and 6 days of exposure were 2.2- and 4.7-fold that of control cells. The stimulatory effect of IL-6 on hPL release and hPL mRNA levels was dose dependent, with a minimal effective dose of 50 U/ml. IL-1 beta, which is known to stimulate IL-6 production by human trophoblast cells, also stimulated dose-dependent increases in hPL release and hPL mRNA levels. IL-6 (500 U/ml) had no effect on trophoblast differentiation, but stimulated a 20-fold increase in hPL promoter activity in BeWo choriocarcinoma cells transfected transiently with a plasmid containing 2.3 kilobases of the hPL promoter coupled to the chloramphenicol acetyltransferase gene. In addition, BeWo cells exposed to IL-6 (500 U/ml) for 3 and 6 days contained 2.4- and 3.2-fold more hPL mRNA levels than control cells. Because placental macrophages and syncytiotrophoblast cells release IL-6, these results strongly suggest an autocrine/paracrine role for IL-6 in the regulation of hPL release. The increase in hPL release appears to be due at least in part to an increase in hPL gene expression.