Interleukin-1b induces glycosaminoglycan synthesis via the prostaglandin E2 pathway in cultured human cervical ®broblasts

The aim of this study was to identify, in cultured human cervical ®broblasts, the mechanisms by which interleukin (IL)-1b 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-1b induced a signi®cant (P < 0.05) dose-dependent increase in GAG synthesis. IL-1b (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 con®rmed that NS398, a selective COX-2 inhibitor, dose-dependently blocked PGE2 augmentation following IL-1b treatment. AH23848, the selective EP4 receptor antagonist, completely abolished IL-1b-induced GAG synthesis, whereas AH6809, an EP2 receptor antagonist, had no effect on the stimulatory effects of IL-1b. Furthermore, we demonstrated that 6 h exposure to IL-1b 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 ®ndings indicate that IL-1b not only induced GAG synthesis by increasing COX-2 protein expression and the subsequent PGE2 production but also enhanced the responsiveness of cervical ®broblasts 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.