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

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 p47^phox/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.