The COX-2-derived PGE 2 autocrine contributes to bradykinin-induced matrix metalloproteinase-9 expression and astrocytic
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RESEARCH
The COX‑2‑derived P GE2 autocrine contributes to bradykinin‑induced matrix metalloproteinase‑9 expression and astrocytic migration via STAT3 signaling Tsong‑Hai Lee1†, Pei‑Shan Liu2†, Ming‑Ming Tsai3,4†, Jiun‑Liang Chen5, Su‑Jane Wang6 and Hsi‑Lung Hsieh3,7*
Abstract Background: The matrix metalloproteinase-9 (MMP-9) is up-regulated by several proinflammatory mediators in the central nervous system (CNS) diseases. Increasing reports show that MMP-9 expression is an inflammatory biomarker of several CNS disorders, including the CNS inflammation and neurodegeneration. Bradykinin (BK) is a common proinflammatory mediator and elevated in several brain injury and inflammatory disorders. The raised BK may be detrimental effects on the CNS that may aggravate brain inflammation through MMP-9 up-regulation or cyclooxy‑ genase-2 (COX-2)-derived prostaglandin E2 (PGE2) production in brain astrocytes. However, the relationship between BK-induced MMP-9 expression and COX-2-derived PGE2 release in brain astrocytes remains unclear. Methods: Herein we used rat brain astrocytes (RBA) to investigate the role of the COX-2/PGE2 system in BK-induced MMP-9 expression. We used zymographic, RT-PCR, EIA, and Western blotting analyses to confirm that BK induces MMP-9 expression via a COX-2/PGE2-dependent pathway. Results: Our results show activation of native COX-2 by BK led to PGE2 production and release. Subsequently, P GE2 induced MMP-9 expression via PGE2 receptor (EP)-mediated c-Src, Jak2, ERK1/2, and then activated signal transducer and activator of transcription 3 (STAT3) signaling pathway. Finally, up-regulation of MMP-9 by BK via the pathway may promote astrocytic migration. Conclusion: These results demonstrated that a novel autocrine pathway for BK-induced MMP-9 protein expression is mediated through activation of STAT3 by native COX-2/PGE2-mediated c-Src/Jak2/ERK cascades in brain astrocytes. Keywords: Bradykinin, Matrix metalloproteinase-9, COX-2/PGE2 autocrine, STAT3, Brain astrocytes, Neuroinflammation
*Correspondence: [email protected] † Tsong-Hai Lee, Pei-Shan Liu, and Ming-Ming Tsai have contributed equally to this work 3 Department of Nursing, Division of Basic Medical Sciences, Research Center for Chinese Herbal Medicine, Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology, 261 Wenhua 1st Road, Guishan, Taoyuan, Taiwan Full list of author information is available at the end of the article
Background The cyclooxygenase-2 (COX-2), known as prostaglandin (PG)-endoperoxide synthase, is inducible expressed in several tissues by various stimuli to promote PGs biosynthesis, PGE2 especially, during inflammatory responses in several cell types [1–4]. Previous studies have shown that overexpression of COX-2 is detected in various inflammatory tissues including macrophages and vascular cells of patients with atherosclerosis. Several evidences have
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