Interleukin-1β induces glycosaminoglycan synthesis via the prostaglandin E2 pathway in cultured human cervical fibroblasts
Interleukin-1β induces glycosaminoglycan synthesis via the prostaglandin E2 pathway in cultured human cervical fibroblasts
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DOI：
10.1093/molehr/gag007
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发表时间：
2003-01-01
影响因子：
4
通讯作者：
Cabrol, D
中科院分区：
文献类型：
--
作者：
Schmitz, T;Leroy, MJ;Cabrol, D
本研究的目的是在培养的人宫颈成纤维细胞中，确定白细胞介素（IL）-1 β诱导糖胺聚糖（GAG）合成的机制，并探讨前列腺素E-2（PGE（2））在此过程中的假定作用。细胞暴露于IL-1 β 24 h可诱导显著（P < 0.05）剂量依赖性GAG合成增加。IL-1 β（1 ng/ml）诱导治疗后6 h环氧化酶-2（考克斯-2）蛋白的表达，同时PGE（2）的产生增加了7.5倍。我们证实，选择性考克斯-2抑制剂NS 398剂量依赖性地阻断IL-1 β治疗后PGE（2）的增加。选择性EP 4受体拮抗剂AH 23848完全阻断IL-1 β诱导的GAG合成，而EP 2受体拮抗剂AH 6809对IL-1 β的刺激作用无影响。此外，我们表明，6小时暴露于IL-1 β诱导EP 4受体mRNA表达的显着增加和EP 1受体mRNA的减少，但对EP 2和EP 3受体转录本的表达没有影响。总之，这些发现表明IL-1 β不仅通过增加考克斯-2蛋白表达和随后的PGE（2）产生来诱导GAG合成，而且通过选择性上调EP 4受体mRNA表达来增强宫颈成纤维细胞对PGE（2）的反应性。这些结果提示PGE（2）可能通过EP 4受体以自分泌/旁分泌方式调节人宫颈成熟。
The aim of this study was to identify, in cultured human cervical fibroblasts, the mechanisms by which interleukin (IL)-1beta induces the synthesis of glycosaminoglycans (GAG) and to explore the putative role of prostaglandin E-2 (PGE(2)) in this process. Exposure of the cells for 24 h to IL-1beta induced a significant (P < 0.05) dose-dependent, increase in GAG synthesis. IL-1beta (1 ng/ml) induced the expression of cyclooxygenase-2 (COX-2) protein 6 h after treatment, accompanied by a 7.5-fold increase in PGE(2) production. We confirmed that NS398, a selective COX-2 inhibitor, dose-dependently blocked PGE(2) augmentation following IL-1beta treatment. AH23848, the selective EP4 receptor antagonist, completely abolished IL-1beta-induced GAG synthesis, whereas AH6809, an EP2 receptor antagonist, had no effect on the stimulatory effects of IL-1beta. Furthermore, we demonstrated that 6 h exposure to IL-1beta 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-1beta not only induced GAG synthesis by increasing COX-2 protein expression and the subsequent PGE(2) production but also enhanced the responsiveness of cervical fibroblasts to PGE(2) by selectively up-regulating EP4 receptor mRNA expression. These results suggest that PGE(2) may regulate human cervical ripening in an autocrine/paracrine manner via EP4 receptors.