Kabashima Kenji, Nagamachi Miyako, Honda Tetsuya, Nishigori Chikako, Miyachi Yoshiki, Tokura Yoshiki, Narumiya Shuh
Department of Pharmacology, Kyoto University Graduate School of Medicine, Sakyo, Kyoto, Japan.
Lab Invest. 2007 Jan;87(1):49-55. doi: 10.1038/labinvest.3700491. Epub 2006 Oct 30.
Keratinocytes are the major target of sunlight, and they produce prostaglandin (PG) E(2) upon ultraviolet (UV) exposure. Although indomethacin, one of cyclooxygenase inhibitors, is known to suppress UV-induced acute skin inflammation, it remains uncertain whether endogenous PGE(2) is responsible for UV-induced skin inflammation, and which subtype of PGE(2) receptors mediates this process. UV-induced skin inflammation was investigated by using genetically and pharmacologically PGE(2) receptor-deficient mice. We applied UV-induced skin inflammation model to genetical and pharmacological PGE(2) receptor-deficient mice. We exposed UVB on these mice at 5 kJ/m(2), and examined the ear swelling and the histological findings. We also measured the blood flow using a laser doppler device to assess the intensity of UVB-induced inflammatory change. The UV-induced ear swelling at 48 h after exposure was significantly reduced in EP2(-/-), EP4(-/-) or wild-type mice treated with the EP4 antagonist compared to control mice. Consistently, inflammatory cell infiltration into the local skin, and local blood flow after UV exposure were significantly reduced by EP2 or EP4 signaling blockade. These data suggest that PGE(2)-EP2/EP4 signaling is mandatory in UV-induced acute skin inflammation, presumably by enhancing blood flow in the microenvironment.
角质形成细胞是阳光的主要作用靶点，紫外线（UV）照射后它们会产生前列腺素（PG）E2。虽然已知环氧化酶抑制剂之一的吲哚美辛可抑制紫外线诱导的急性皮肤炎症，但内源性PGE2是否导致紫外线诱导的皮肤炎症以及PGE2受体的哪种亚型介导这一过程仍不确定。我们使用基因工程和药理学方法构建的PGE2受体缺陷小鼠来研究紫外线诱导的皮肤炎症。我们将紫外线诱导的皮肤炎症模型应用于基因工程和药理学方法构建的PGE2受体缺陷小鼠。我们以5 kJ/m2的剂量对这些小鼠进行紫外线B（UVB）照射，并检查耳部肿胀情况和组织学表现。我们还使用激光多普勒装置测量血流量，以评估UVB诱导的炎症变化强度。与对照小鼠相比，在EP2（-/-）、EP4（-/-）小鼠或用EP4拮抗剂处理的野生型小鼠中，紫外线照射后48小时诱导的耳部肿胀明显减轻。同样，通过EP2或EP4信号阻断，紫外线照射后局部皮肤的炎症细胞浸润和局部血流量显著减少。这些数据表明，PGE2-EP2/EP4信号在紫外线诱导的急性皮肤炎症中起关键作用，可能是通过增强微环境中的血流量来实现的。
