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Biochemistry - Diabetes and Endocrinology - Molecular Biology - Obstetrics

Caffeine Reduces 11ß-Hydroxysteroid Dehydrogenase Type 2 Expression in Human Trophoblast Cells through the Adenosine A2B Receptor
Published: Monday, June 11, 2012
Author: Saina Sharmin et al.

by Saina Sharmin, Haiyan Guan, Andrew Scott Williams, Kaiping Yang

Maternal caffeine consumption is associated with reduced fetal growth, but the underlying molecular mechanisms are unknown. Since there is evidence that decreased placental 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2) is linked to fetal growth restriction, we hypothesized that caffeine may inhibit fetal growth partly through down regulating placental 11ß-HSD2. As a first step in examining this hypothesis, we studied the effects of caffeine on placental 11ß-HSD2 activity and expression using our established primary human trophoblast cells as an in vitro model system. Given that maternal serum concentrations of paraxanthine (the primary metabolite of caffeine) were greater in women who gave birth to small-for-gestational age infants than to appropriately grown infants, we also studied the effects of paraxanthine. Our main findings were: (1) both caffeine and paraxanthine decreased placental 11ß-HSD2 activity, protein and mRNA in a concentration-dependent manner; (2) this inhibitory effect was mediated by the adenosine A2B receptor, since siRNA-mediated knockdown of this receptor prevented caffeine- and paraxanthine-induced inhibition of placental 11ß-HSD2; and (3) forskolin (an activator of adenyl cyclase and a known stimulator of 11ß-HSD2) abrogated the inhibitory effects of both caffeine and paraxanthine, which provides evidence for a functional link between exposure to caffeine and paraxanthine, decreased intracellular levels of cAMP and reduced placental 11ß-HSD2. Taken together, these findings reveal that placental 11ß-HSD2 is a novel molecular target through which caffeine may adversely affect fetal growth. They also uncover a previously unappreciated role for the adenosine A2B receptor signaling in regulating placental 11ß-HSD2, and consequently fetal development.