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NADPH oxidase 2-derived reactive oxygen species signal contributes to bradykinin-induced matrix metalloproteinase-9 expression and cell migration in brain astrocytes

Chih-Chung Lin1, Hsi-Lung Hsieh2, Ruey-Horng Shih3, Pei-Ling Chi3, Shin-Ei Cheng3, Jin-Chung Chen3 and Chuen-Mao Yang3*

Author Affiliations

1 Department of Anesthetics, College of Medicine, Chang Gung University and Chang Gung Memorial Hospital at Linkuo, Kwei-San, Tao-Yuan, Taiwan

2 Department of Nursing, Division of Basic Medical Sciences, Chang Gung University of Science and Technology, Tao-Yuan, Taiwan

3 Department of Physiology and Pharmacology and Health Aging Research Center, College of Medicine, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-San, Tao-Yuan, Taiwan

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Cell Communication and Signaling 2012, 10:35  doi:10.1186/1478-811X-10-35

Published: 23 November 2012



Matrix metalloproteinase-9 (MMP-9) plays a crucial role in pathological processes of brain inflammation, injury, and neurodegeneration. Moreover, bradykinin (BK) induces the expression of several inflammatory proteins in brain astrocytes. Recent studies have suggested that increased oxidative stress is implicated in the brain inflammation and injury. However, whether BK induced MMP-9 expression mediated through oxidative stress remains virtually unknown. Herein we investigated the role of redox signals in BK-induced MMP-9 expression in rat brain astrocytes (RBA-1 cells).


In the study, we first demonstrated that reactive oxygen species (ROS) plays a crucial role in BK-induced MMP-9 expression in cultured brain astrocytes (in vitro) and animal brain tissue (in vivo) models. Next, BK-induced MMP-9 expression is mediated through a Ca2+-mediated PKC-α linking to p47phox/NADPH oxidase 2 (Nox2)/ROS signaling pathway. Nox2-dependent ROS generation led to activation and up-regulation of the downstream transcriptional factor AP-1 (i.e. c-Fos and c-Jun), which bound to MMP-9 promoter region, and thereby turned on transcription of MMP-9 gene. Functionally, BK-induced MMP-9 expression enhanced astrocytic migration.


These results demonstrated that in RBA-1 cells, activation of AP-1 (c-Fos/c-Jun) by the PKC-α-mediated Nox2/ROS signals is essential for up-regulation of MMP-9 and cell migration enhanced by BK.

Brain inflammation; Astrocytes; Bradykinin; Matrix metalloproteinase-9; NADPH oxidase; Reactive oxygen species