Induction of Gαs contributes to the paradoxical stimulation of cytosolic phospholipase A expression by cortisol in human amnion fibroblasts

Chunming Guo, Jianneng Li, Leslie Myatt, Xiaoou Zhu, Kang Sun

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Cytosolic phospholipase A (cPLA) catalyzes the formation of arachidonic acid in prostaglandin synthesis. In contrast to the well-described down-regulation of cPLA, up-regulation of cPLA by glucocorticoids has been reported in human amnion fibroblasts, which may play a key role in parturition. The mechanisms underlying this paradoxical induction of cPLA by glucocorticoids remain largely unknown. Using cultured human amnion fibroblasts, we found that the induction of cPLA by cortisol required ongoing transcription and synthesis of at least one other protein. The induction of cPLA by cortisol was abolished by mutagenesis of a glucocorticoid response element (GRE) in the promoter. The same GRE was found mediating the classical inhibition of cPLA expression by cortisol in human fetal lung fibroblasts (HFL-1). Cortisol increased Gαs expression in amnion fibroblasts but not in HFL-1 cells. Inhibition of Gαs with NF449 attenuated the phosphorylation of cAMP response element-binding protein-1 (CREB-1) and the induction of cPLA by cortisol in amnion fibroblasts. Both glucocorticoid receptor (GR) and CREB-1 were found bound to the GRE upon cortisol stimulation of amnion fibroblasts. The induction of cPLA by cortisol was blocked by GR antagonist RU486 or protein kinase A inhibitor H89 or dominantnegative CREB-1. In conclusion, cortisol activates the cAMP/protein kinase A/CREB-1 pathway via Gαs induction, and the phosphorylated CREB-1 interacts with GR at the GRE to promote cPLA expression in amnion fibroblasts.

Original languageEnglish (US)
Pages (from-to)1052-1061
Number of pages10
JournalMolecular Endocrinology
Volume24
Issue number5
DOIs
StatePublished - May 1 2010

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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