Hypoxia-mediated downregulation of human chorionic gonadotropin subunit mRNA expression in cytotrophoblastic JAr cells

Abstract

Summary Oxygen tension plays a role in regulating placental differentiation and function. To begin to understand the mechanisms of hypoxia-mediated gene expression in trophoblast cells we investigated the regulation of hCG in cytotrophoblastic JAr cells cultured at low oxygen tension. We demonstrated that constitutive and inducible secretion of the hormone are respressed at the level of mRNA abundancy of both subunit genes, α and β. Transcripts, however, which encode the glycolytic enzyme GAPDH increase in the hypoxic environment indicating adaptation to the anaerobic conditions. Repression of hormone mRNAs may involve modulations in activating signal transduction pathways resulting in downregulation of transcriptional activity. Subtle changes in cellular cAMP are detectable, which, however, do not explain downregulation of α/β hCG mRNA expression at low oxygen supply. Furthermore, elevation of cAMP cannot overcome hypoxic suppression, suggesting that a cAMP/protein kinase-A-mediated signal transduction pathway is not involved. Although we detected IL-1- and hypoxia-dependent induction of IL-6 mRNA, IL-6 secretion is reduced in the hypoxic environment. IL-1-inducible hCG expression, therefore might be affected by changes in IL-6/IL-6 receptor-dependent tyrosine phosphorylation. Actinomycin-D mRNA stability assays revealed that α and βhCG mRNA half-lives do not decline in the hypoxic environment, suggesting that the decrease in transcriptional activities of both subunit genes could be the major cause of reduced hCG expression at low oxygen pressure.