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IL-1β Induces MMP-9-Dependent Brain Astrocytic Migration via Transactivation of PDGF Receptor/NADPH Oxidase 2-Derived Reactive Oxygen Species Signals

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Abstract

Matrix metalloproteinase-9 (MMP-9) plays a crucial role in pathological processes of brain inflammation, injury, and neurodegeneration. Moreover, cytokines such as interleukin-1β (IL-1β) induce expression of several inflammatory mediators in brain astrocytes, which may be important for brain inflammatory disorders. Recent studies have implicated that increased oxidative stress may contribute to the brain injury and inflammation. However, whether IL-1β-induced MMP-9 expression mediated through oxidative stress remains unclear. Therefore, we investigated the role of redox signals in IL-1β-induced MMP-9 expression in rat brain astrocytes (RBA-1 cells). Herein, we first demonstrated that reactive oxygen species (ROS) play a crucial role in ILβ-induced MMP-9 expression by zymography, real-time PCR, and ROS staining in cultured RBA-1 cells. Next, IL-1β-induced MMP-9 expression is mediated through a c-Src-mediated transactivation of PDGFR/PI3K/Akt cascade linking to p47phox/NADPH oxidase 2 (Nox2)/ROS signaling pathway. Nox2-dependent ROS generation led to activation of MAPKs and the downstream transcription factors NF-κB and AP-1 (i.e., ATF2), which enhanced MMP-9 promoter activity, and thereby turned on transcription of MMP-9 gene. Functionally, IL-1β-induced MMP-9 expression promoted astrocytic migration. These results demonstrated that in RBA-1 cells, activation of NF-κB and AP-1 (ATF2) by the c-Src/PDGFR/PI3K/Akt-mediated Nox2/ROS/MAPKs signals is required for upregulation of MMP-9 and cell migration enhanced by IL-1β.

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Acknowledgments

This work was supported by National Science Council, Taiwan; Grant number: NSC102-2321-B-182-011, NSC101-2320-B-182-039-MY3, NSC101-2314-B-182-182A-112, and NSC102-2320-B-255-005-MY3; Chang Gung Medical Research Foundation, Grant number: CMRPD1B0331, CMRPD1C0102, CMRPD1B0383, CMRPD1C0562, CMRPG3B1093, CMRPG3C1302, CMRPG5C0061, CMRPF1C0191, and CMRPF1A0063; and the Ministry of Education, Taiwan; Grant number: EMRPD1D0231 and EMRPD1D0241.

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Authors and Affiliations

  1. 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

    Chuen-Mao Yang & Ping-Hsien Yu

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

    Hsi-Lung Hsieh

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

    Chih-Chung Lin & Shiau-Wen Liu

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  1. Chuen-Mao Yang
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  2. Hsi-Lung Hsieh
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Correspondence to Chuen-Mao Yang.

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Yang, CM., Hsieh, HL., Yu, PH. et al. IL-1β Induces MMP-9-Dependent Brain Astrocytic Migration via Transactivation of PDGF Receptor/NADPH Oxidase 2-Derived Reactive Oxygen Species Signals. Mol Neurobiol 52, 303–317 (2015). https://doi.org/10.1007/s12035-014-8838-y

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