Interleukin-1beta induces glycosaminoglycan synthesis via the prostaglandin E2 pathway in cultured human cervical fibroblasts

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Abstract
The aim of this study was to identify, in cultured human cervical fibroblasts, the mechanisms by which interleukin (IL)‐1β 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‐1β induced a significant (P < 0.05) dose‐dependent increase in GAG synthesis. IL‐1β (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‐1β treatment. AH23848, the selective EP4 receptor antagonist, completely abolished IL‐1β‐induced GAG synthesis, whereas AH6809, an EP2 receptor antagonist, had no effect on the stimulatory effects of IL‐1β. Furthermore, we demonstrated that 6 h exposure to IL‐1β 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‐1β 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.