Molecular Human Reproduction, Vol. 9, No. 1, 1-8,
January 2003
© 2003 European Society of Human Reproduction and Embryology
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Interleukin-1ß induces glycosaminoglycan synthesis via the prostaglandin E2 pathway in cultured human cervical fibroblasts
Submitted on February 7, 2002; resubmitted on August 7, 2002. accepted on October 31, 2002
1 INSERM U 361, Université René Descartes, Paris and 2 Maternité Port-Royal, Hopital Cochin, AP-HP, Université René Descartes, Paris, France 3 To whom correspondence should be addressed at: INSERM U 361, Pavillon Baudelocque, 123, Bd de Port-Royal, F-75014 Paris, France. e-mail: tsn{at}club-internet.fr
The aim of this study was to identify, in cultured human cervical fibroblasts, the mechanisms by which interleukin (IL)-1ß induces the synthesis of glycosaminoglycans (GAG) and to explore the putative role of prostaglandin E2 (PGE2) in this process. Exposure of the cells for 24 h to IL-1ß induced a significant (P < 0.05) dose-dependent increase in GAG synthesis. IL-1ß (1 ng/ml) induced the expression of cyclooxygenase-2 (COX-2) protein 6 h after treatment, accompanied by a 7.5-fold increase in PGE2 production. We confirmed that NS398, a selective COX-2 inhibitor, dose-dependently blocked PGE2 augmentation following IL-1ß treatment. AH23848, the selective EP4 receptor antagonist, completely abolished IL-1ß-induced GAG synthesis, whereas AH6809, an EP2 receptor antagonist, had no effect on the stimulatory effects of IL-1ß. Furthermore, we demonstrated that 6 h exposure to IL-1ß induced a notable increase in EP4 receptor mRNA expression and a decrease in EP1 receptor mRNA but had no effect on the expression of EP2 and EP3 receptor transcripts. In conclusion, these findings indicate that IL-1ß not only induced GAG synthesis by increasing COX-2 protein expression and the subsequent PGE2 production but also enhanced the responsiveness of cervical fibroblasts to PGE2 by selectively up-regulating EP4 receptor mRNA expression. These results suggest that PGE2 may regulate human cervical ripening in an autocrine/paracrine manner via EP4 receptors.
Key words: cervical ripening/EP receptors/glycosaminoglycan/IL-1ß/prostaglandin E2
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