Reactive oxygen species (ROS), a redox signal, are produced by various enzymatic reactions and chemical processes, which are essential for many physiological functions and act as second messengers. However, accumulating evidence has implicated the pathogenesis of several human diseases including neurodegenerative disorders related to increased oxidative stress. Under pathological conditions, increasing ROS production can regulate the expression of diverse inflammatory mediators during brain injury. Elevated levels of several proinflammatory factors including cytokines, peptides, pathogenic structures, and peroxidants in the central nervous system (CNS) have been detected in patients with neurodegenerative diseases such as Alzheimer’s disease (AD). These proinflammatory factors act as potent stimuli in brain inflammation through upregulation of diverse inflammatory genes, including matrix metalloproteinases (MMPs), cytosolic phospholipase A₂(cPLA₂), cyclooxygenase-2 (COX-2), and adhesion molecules. To date, the intracellular signaling mechanisms underlying the expression of target proteins regulated by these factors are elusive. In this review, we discuss the mechanisms underlying the intracellular signaling pathways, especially ROS, involved in the expression of several inflammatory proteins induced by proinflammatory factors in brain resident cells. Understanding redox signaling transduction mechanisms involved in the expression of target proteins and genes may provide useful therapeutic strategies for brain injury, inflammation, and neurodegenerative diseases.

Background: Transforming growth factor-β (TGF-β) and matrix metalloproteinases (MMPs) are the multifunctional factors during diverse physiological and pathological processes including development, wound healing, proliferation, and cancer metastasis. Both TGF-β and MMPs have been shown to play crucial roles in brain pathological changes. Thus, we investigated the molecular mechanisms underlying TGF-β1-induced MMP-9 expression in brain astrocytes. Methods: Rat brain astrocytes (RBA-1) were used. MMP-9 expression was analyzed by gelatin zymography and RT-PCR. The involvement of signaling molecules including MAPKs and NF-κB in the responses was investigated using pharmacological inhibitors and dominant negative mutants, determined by western blot and gene promoter assay. The functional activity of MMP-9 was evaluated by cell migration assay. Results: Here we report that TGF-β1 induces MMP-9 expression and enzymatic activity via a TGF-β receptor-activated reactive oxygen species (ROS)-dependent signaling pathway. ROS production leads to activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun-N-terminal kinase (JNK) and then activation of the NF-κB transcription factor. Activated NF-κB turns on transcription of the MMP-9 gene. The rat MMP-9 promoter, containing a NF-κB cis-binding site, was identified as a crucial domain linking to TGF-β1 action. Conclusions: Collectively, in RBA-1 cells, activation of ERK1/2- and JNK-NF-κB cascades by a ROS-dependent manner is essential for MMP-9 up-regulation/activation and cell migration induced by TGF-β1. These findings indicate a new regulatory pathway of TGF-β1 in regulating expression of MMP-9 in brain astrocytes, which is involved in physiological and pathological tissue remodeling of central nervous system.

BACKGROUND AND PURPOSE Interleukin (IL)‐1β‐induced matrix metalloproteinase (MMP‐9) expression is regulated by mitogen activated protein kinases (MAPKs) and NF‐κB. IL‐1β also stimulates transactivation of growth factor receptors and phosphatidylinositol 3‐kinase (PI3K)/Akt., leading to the expression of inflammatory proteins. Here, we investigated whether these transactivation mechanisms participated in IL‐1β‐induced MMP‐9 expression in A549 cells. EXPERIMENTAL APPROACH A549 cells were treated with/without pharmacological inhibitors and neutralizing antibody or transfected with dominant negative mutants and siRNA of particular protein kinases before stimulation with IL‐1β. Cell migration was measured by in vitro scratch assay. Expression and enzymatic activity of MMP‐9 were analysed by Western blot and gelatin zymography. Transcriptional activity of MMP‐9 was analysed by RT‐PCR, chromatin immunoprecipitation and promoter assays. KEY RESULTS Inhibition of MMP‐9 expression by inhibitors of Src (PP1), platelet‐derived growth factor (PDGF) receptor and epithelial growth factor (EGF) receptor or transfection with siRNA for Src and Akt prevented IL‐1β‐induced migration of A549 cells. These tyrosine kinases were involved through phosphorylation of Src, PDGF, or EGF receptors (EGFRs) via the formation of Src/PDGFR or Src/EGFR complexes, attenuated by PP1. IL‐1β‐induced MMP‐9 expression through EGFR transactivation was diminished by inhibitors of MMPs and heparin‐binding EGF‐like factor (HB‐EGF), or a neutralizing HB‐EGF antibody. IL‐1β‐stimulated activation and translocation of Akt and NF‐κB (p65); the recruitment of activated NF‐κB (p65) to the MMP‐9 promoter region was attenuated by LY294002. CONCLUSIONS AND IMPLICATIONS IL‐1β‐induced MMP‐9 expression and cell migration was mediated through c‐Src‐dependent transactivation of EGFR/PDGFR/PI3K/Akt linking to the NF‐κB pathway in A549 cells.