Up-regulation of COX-2/PGE(2) by endothelin-1 via MAPK-dependent NF-kB pathway in mouse brain microvascular endothelial cells

作者：Lin Chih Chung; Hsieh Hsi Lung; Shih Ruey Horng; Chi Pei Ling; Cheng Shin Ei; Yang Chuen Mao^*

来源：Cell Communication and Signaling, 2013, 11(1): 8.

DOI：10.1186/1478-811X-11-8

• Endothelin-1
• COX-2
• MAPK
• NF-kappa B
• Brain microvascular endothelial cells

Background: Endothelin-1 (ET-1) is a proinflammatory mediator and elevated in the regions of several brain injury and inflammatory diseases. The deleterious effects of ET-1 on endothelial cells may aggravate brain inflammation mediated through the regulation of cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) system in various cell types. However, the signaling mechanisms underlying ET-1-induced COX-2 expression in brain microvascular endothelial cells remain unclear. Herein we investigated the effects of ET-1 in COX-2 regulation in mouse brain microvascular endothelial (bEnd.3) cells. %26lt;br%26gt;Results: The data obtained with Western blotting, RT-PCR, and immunofluorescent staining analyses showed that ET-1-induced COX-2 expression was mediated through an ETB-dependent transcriptional activation. Engagement of G(i)-and G(q)-protein-coupled ETB receptors by ET-1 led to phosphorylation of ERK1/2, p38 MAPK, and JNK1/2 and then activated transcription factor NF-kappa B. Moreover, the data of chromatin immunoprecipitation (ChIP) and promoter reporter assay demonstrated that the activated NF-kappa B was translocated into nucleus and bound to its corresponding binding sites in COX-2 promoter, thereby turning on COX-2 gene transcription. Finally, up-regulation of COX-2 by ET-1 promoted PGE(2) release in these cells. %26lt;br%26gt;Conclusions: These results suggested that in mouse bEnd.3 cells, activation of NF-kappa B by ETB-dependent MAPK cascades is essential for ET-1-induced up-regulation of COX-2/PGE(2) system. Understanding the mechanisms of COX-2 expression and PGE(2) release regulated by ET-1/ETB system on brain microvascular endothelial cells may provide rationally therapeutic interventions for brain injury or inflammatory diseases.

• 出版日期2013-1-23
• 单位长春大学