Iwamoto Junichi, Takahashi Kimiko, Mizokami Yuji, Otsubo Toshiya, Miura Syuuhei, Narasaka Toshiaki, Takeyama Hiroki, Omata Takayuki, Shimokoube Kouichi, Matsuoka Takeshi
Fifth Department of Internal Medicine, Tokyo Medical University, Inashiki, Ibaraki, Japan.
Dig Dis Sci. 2003 Dec;48(12):2247-56. doi: 10.1023/b:ddas.0000007859.10680.b1.
In acute inflammatory condition, little is known about the expression of the urokinase-type plasminogen activator (uPA) and its receptor (uPAR) in the gastric fibroblasts. To clarify the role of human gastric fibroblasts in acute inflammatory conditions such as gastric ulcer, the effects of interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha on the expression of uPA and uPAR, which were suggested to be associated with tissue remodeling, in gastric fibroblasts were investigated. The expression level of uPA mRNA and the amount of uPA antigen increased significantly on treatment with each concentration of IL-1beta (1 and 10 ng/ml) and 10 ng/ml TNF-alpha. On the other hand, the amounts of uPA antigen on cell surfaces were not affected significantly by IL-1beta and TNF-alpha stimulation. The expression level of uPAR mRNA increased in a dose-dependent manner on IL-1beta stimulation. The effect of indomethacin on uPA and uPAR expression in these cells was also examined. When gastric fibroblasts were treated with 50 microM indomethacin, the expression level of uPA mRNA decreased significantly, and the amount of uPA antigen in the culture medium and on cell surfaces decreased significantly with indomethacin in a dose-dependent manner. The increased uPAR mRNA expression caused by IL-1beta was reduced to the basal level by treatment with 50 microM indomethacin. Furthermore, we investigated the role of prostaglandin E2 (PGE2), which is suggested to play major roles in acute inflammation of the stomatch, on uPA and uPAR expression in gastric fibroblasts. The expression level of uPAR mRNA and the amount of uPA antigen on cell surfaces increased in a dose-dependent manner on treatment with PGE2 (10 and 50 ng/ml). These results suggest that uPA and uPAR expression in gastric fibroblasts is involved in the regulating system of PGE2 and that NSAIDs may delay healing of gastric mucosal injury in part through suppressing uPA production via inhibition of endogenous PG production.
在急性炎症状态下，关于尿激酶型纤溶酶原激活剂（uPA）及其受体（uPAR）在胃成纤维细胞中的表达情况所知甚少。为阐明人胃成纤维细胞在胃溃疡等急性炎症状态中的作用，研究了白细胞介素（IL）-1β和肿瘤坏死因子（TNF）-α对胃成纤维细胞中uPA和uPAR表达的影响，uPA和uPAR被认为与组织重塑有关。用每种浓度的IL-1β（1和10 ng/ml）以及10 ng/ml TNF-α处理后，uPA mRNA的表达水平和uPA抗原量显著增加。另一方面，IL-1β和TNF-α刺激对细胞表面uPA抗原量没有显著影响。IL-1β刺激后，uPAR mRNA的表达水平呈剂量依赖性增加。还检测了吲哚美辛对这些细胞中uPA和uPAR表达的影响。当胃成纤维细胞用50 μM吲哚美辛处理时，uPA mRNA的表达水平显著降低，培养基和细胞表面的uPA抗原量也随吲哚美辛呈剂量依赖性显著降低。用50 μM吲哚美辛处理可将IL-1β引起的uPAR mRNA表达增加降低至基础水平。此外，我们研究了前列腺素E2（PGE2）在胃成纤维细胞uPA和uPAR表达上的作用，PGE2被认为在胃的急性炎症中起主要作用。用PGE2（10和50 ng/ml）处理后，uPAR mRNA的表达水平和细胞表面uPA抗原量呈剂量依赖性增加。这些结果表明，胃成纤维细胞中uPA和uPAR的表达参与了PGE2调节系统，非甾体抗炎药可能部分通过抑制内源性前列腺素生成来抑制uPA产生，从而延迟胃黏膜损伤的愈合。
