Bando Y, Noguchi K, Kobayashi H, Yoshida N, Ishikawa I, Izumi Y
Periodontology, Department of Hard Tissue Engineering, Tokyo Medical and Dental University, Tokyo, Japan.
J Periodontal Res. 2009 Jun;44(3):395-401. doi: 10.1111/j.1600-0765.2008.01118.x. Epub 2009 Feb 6.
Prostaglandin E(2), which exerts its actions via EP receptors (EP1, EP2, EP3 and EP4), is a bioactive metabolite of arachidonic acid produced by cyclooxygenase-1 and/or cyclooxygenase-2. Interleukin-1alpha induces prostaglandin E(2) production via cyclooxygenase-2 in human periodontal ligament cells. Vascular endothelial growth factor is a key regulator of physiologic as well as pathologic angiogenesis and has been indicated to be involved in the pathology of periodontal diseases. In the present study, we investigated whether interleukin-1alpha induced vascular endothelial growth factor production in human periodontal ligament cells and whether cyclooxygenase-2-derived prostaglandin E(2) regulated interleukin-1alpha-induced vascular endothelial growth factor production.
Human periodontal ligament cells were obtained from extracted teeth of periodontally healthy subjects. After pre-incubation with a nonselective cyclooxygenase-1/2 inhibitor, indomethacin or a selective cyclooxygenase-2 inhibitor (NS-398), periodontal ligament cells were treated with or without interleukin-1alpha, prostaglandin E(2), various EP receptor agonists and dibutyryl cAMP (a cAMP analogue). The levels of vascular endothelial growth factor and prostaglandin E(2) in the culture supernatant were measured by enzyme-linked immunosorbent assay. The vascular endothelial growth factor mRNA expression was evaluated by semiquantitative reverse transcription-polymerase chain reaction.
Interleukin-1alpha induced vascular endothelial growth factor production in a dose-dependent and time-dependent manner. The interleukin-1alpha-induced vascular endothelial growth factor mRNA and protein expression was inhibited to the same extent by indomethacin and NS-398. Indomethacin and NS-398 completely inhibited interleukin-1alpha-induced prostaglandin E(2) production. Exogenous prostaglandin E(2), butaprost (an EP2 receptor agonist) and dibutyryl cAMP abolished the inhibitory effect of indomethacin on interleukin-1alpha-induced vascular endothelial growth factor production.
We suggest that interleukin-1alpha induced vascular endothelial growth factor production via cyclooxygenase-2-derived prostaglandin E(2) in human periodontal ligament cells. The interleukin-1alpha/prostaglandin E(2) pathway might regulate vascular endothelial growth factor production in periodontal lesions.
前列腺素E2是由环氧化酶-1和/或环氧化酶-2产生的花生四烯酸的生物活性代谢产物，它通过EP受体（EP1、EP2、EP3和EP4）发挥作用。白细胞介素-1α可通过环氧化酶-2诱导人牙周膜细胞产生前列腺素E2。血管内皮生长因子是生理性及病理性血管生成的关键调节因子，已被证实参与牙周疾病的病理过程。在本研究中，我们调查了白细胞介素-1α是否能诱导人牙周膜细胞产生血管内皮生长因子，以及环氧化酶-2衍生的前列腺素E2是否能调节白细胞介素-1α诱导的血管内皮生长因子的产生。
从牙周健康受试者拔除的牙齿中获取人牙周膜细胞。在用非选择性环氧化酶-1/2抑制剂吲哚美辛或选择性环氧化酶-2抑制剂（NS-398）预孵育后，对牙周膜细胞进行有无白细胞介素-1α、前列腺素E2、各种EP受体激动剂及二丁酰环磷腺苷（一种环磷腺苷类似物）的处理。通过酶联免疫吸附测定法测量培养上清液中血管内皮生长因子和前列腺素E2的水平。通过半定量逆转录-聚合酶链反应评估血管内皮生长因子mRNA的表达。
白细胞介素-1α以剂量和时间依赖性方式诱导血管内皮生长因子的产生。吲哚美辛和NS-398对白细胞介素-1α诱导的血管内皮生长因子mRNA和蛋白表达的抑制程度相同。吲哚美辛和NS-398完全抑制白细胞介素-1α诱导的前列腺素E2的产生。外源性前列腺素E2、布他前列素（一种EP2受体激动剂）和二丁酰环磷腺苷消除了吲哚美辛对白细胞介素-1α诱导的血管内皮生长因子产生的抑制作用。
我们认为白细胞介素-1α通过环氧化酶-2衍生的前列腺素E2在人牙周膜细胞中诱导血管内皮生长因子的产生。白细胞介素-1α/前列腺素E2途径可能调节牙周病变中血管内皮生长因子的产生。
