Caffeine reduces 11β-hydroxysteroid dehydrogenase type 2 expression in human trophoblast cells through the adenosine A(2B) receptor.
Maternal caffeine consumption is associated with reduced fetal growth, but the underlying molecular mechanisms are unknown. Since there is evidence that decreased placental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) is linked to fetal growth restriction, we hypothesized that caffeine may inhibit fetal growth partly through down regulating placental 11β-HSD2. As a first step in examining this hypothesis, we studied the effects of caffeine on placental 11β-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 11β-HSD2 activity, protein and mRNA in a concentration-dependent manner; (2) this inhibitory effect was mediated by the adenosine A(2B) receptor, since siRNA-mediated knockdown of this receptor prevented caffeine- and paraxanthine-induced inhibition of placental 11β-HSD2; and (3) forskolin (an activator of adenyl cyclase and a known stimulator of 11β-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 11β-HSD2. Taken together, these findings reveal that placental 11β-HSD2 is a novel molecular target through which caffeine may adversely affect fetal growth. They also uncover a previously unappreciated role for the adenosine A(2B) receptor signaling in regulating placental 11β-HSD2, and consequently fetal development.
Children's Health Research Institute, Department of Obstetrics, The University of Western Ontario, London, Ontario, Canada.
Saina
S
Sharmin
Haiyan
H
Guan
Andrew Scott
AS
Williams
Kaiping
K
Yang
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000378:metabolism*; D000704:Analysis of Variance; D015153:Blotting, Western; D002110:Caffeine / Q000378:metabolism / Q000494:pharmacology*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000235:genetics; D055785:Gene Knockdown Techniques; D006801:Humans; D066298:In Vitro Techniques; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D043704:Receptor, Adenosine A2B / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013806:Theophylline / Q000378:metabolism / Q000494:pharmacology*; D014327:Trophoblasts / Q000201:enzymology*
D017931:DNA Primers; D034741:RNA, Small Interfering; D043704:Receptor, Adenosine A2B; D005576:Colforsin; D002110:Caffeine; D013806:Theophylline; D000242:Cyclic AMP; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; C021183:1,7-dimethylxanthine