Urocortin induces interleukin-6 gene expression via cyclooxygenase-2 activity in aortic smooth muscle cells.
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.
Kageyama
Kazunori
K
Department of Endocrinology, Metabolism, and Infectious Diseases, Hirosaki University School of Medicine, Aomori 036-8562, Japan. kkageyama@hkg.odn.ne.jp
Hanada
Komaki
K
Nigawara
Takeshi
T
Moriyama
Takako
T
Terui
Ken
K
Sakihara
Satoru
S
Suda
Toshihiro
T
D000818:Animals; D001011:Aorta; D002460:Cell Line; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011993:Recombinant Fusion Proteins; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D054832:Urocortins
D016861:Cyclooxygenase Inhibitors; D007375:Interleukin-1; D015850:Interleukin-6; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D054832:Urocortins; D003346:Corticotropin-Releasing Hormone; D008156:Luciferases; D051546:Cyclooxygenase 2; D007213:Indomethacin