Kageyama Kazunori, Hanada Komaki, Nigawara Takeshi, Moriyama Takako, Terui Ken, Sakihara Satoru, Suda Toshihiro
Department of Endocrinology, Metabolism, and Infectious Diseases, Hirosaki University School of Medicine, Aomori 036-8562, Japan.
Endocrinology. 2006 Sep;147(9):4454-62. doi: 10.1210/en.2006-0008. Epub 2006 Jun 15.
Corticotropin-releasing factor (CRF) plays a central role in controlling stress-related activity of the hypothalamic-pituitary-adrenal axis. Four CRF-related peptides have been found in mammals: CRF and urocortins (Ucns) 1-3. Ucns bound to CRF(2beta) receptors have a physiological role in the cardiovascular system. We previously found that both Ucn1 and -2 induced accumulation of intracellular cAMP via CRF(2beta) receptor binding and significantly increased IL-6 secretion by A7r5 aortic smooth muscle cells. In the present study, we investigated Ucn effects on IL-6 gene expression and IL-6 synthesis in A7r5 aortic smooth muscle cells. Ucn1 and -2 stimulated IL-6 gene transcription and IL-6 secretion via CRF(2) receptors. Indomethacin, a cyclooxygenase (COX) inhibitor, suppressed IL-6 gene transcription and IL-6 secretion by Ucn1 or -2. NS-398, a COX-2 inhibitor, suppressed IL-6 induction to the same extent as indomethacin. These results suggest that the COX-2 pathway is involved downstream in regulation of Ucn-increased IL-6 gene expression and IL-6 secretion. In addition, COX-2 expression levels were increased at 6 h with the combination of Ucn1 and IL-1, compared with single peptide activation. Ucn1 showed a potent stimulatory effect on IL-6 output, whereas IL-1 alone had no significant effects. However, when Ucn1 was simultaneously used with IL-1, it markedly potentiated the increments in IL-6 output and promoter activity produced by Ucn1. Taken together, these findings indicate that the COX-2 pathway plays a major role in increasing IL-6 levels stimulated by Ucn and IL-1 in A7r5 cells.
促肾上腺皮质激素释放因子（CRF）在控制下丘脑 - 垂体 - 肾上腺轴的应激相关活动中起核心作用。在哺乳动物中已发现四种与CRF相关的肽：CRF和尿皮质素（Ucns）1 - 3。与CRF(2β)受体结合的Ucns在心血管系统中具有生理作用。我们先前发现，Ucn1和 - 2均通过与CRF(2β)受体结合诱导细胞内cAMP积累，并显著增加A7r5主动脉平滑肌细胞的IL - 6分泌。在本研究中，我们研究了Ucn对A7r5主动脉平滑肌细胞中IL - 6基因表达和IL - 6合成的影响。Ucn1和 - 2通过CRF(2)受体刺激IL - 6基因转录和IL - 6分泌。环氧化酶（COX）抑制剂吲哚美辛抑制Ucn1或 - 2诱导的IL - 6基因转录和IL - 6分泌。COX - 2抑制剂NS - 398对IL - 6诱导的抑制程度与吲哚美辛相同。这些结果表明，COX - 2途径参与Ucn增加的IL - 6基因表达和IL - 6分泌的下游调节。此外，与单一肽激活相比，Ucn1和IL - 1联合使用时，COX - 2表达水平在6小时时升高。Ucn1对IL - 6输出具有强大的刺激作用，而单独的IL - 1没有显著影响。然而，当Ucn1与IL - 1同时使用时，它显著增强了Ucn1产生的IL - 6输出和启动子活性的增加。综上所述，这些发现表明COX - 2途径在增加A7r5细胞中由Ucn和IL - 1刺激的IL - 6水平中起主要作用。
