Japanese encephalitis virus induces matrix metalloproteinase-9 expression via a ROS/c-Src/PDGFR/PI3K/Akt/MAPKs-dependent AP-1 pathway in rat brain astrocytes

Abstract

BackgroundJapanese encephalitis virus (JEV) infection is a major cause of acute encephalopathy in children, which destroys central nervous system (CNS) cells, including astrocytes and neurons. Matrix metalloproteinase (MMP)-9 has been shown to degrade components of the basal lamina, leading to disruption of the blood-brain barrier (BBB) and to contribute to neuroinflammatory responses in many neurological diseases. However, the detailed mechanisms of JEV-induced MMP-9 expression in rat brain astrocytes (RBA-1 cells) are largely unclear.MethodsIn this study, the effect of JEV on expression of MMP-9 was determined by gelatin zymography, western blot analysis, RT-PCR, and promoter assay. The involvement of AP-1 (c-Jun and c-Fos), c-Src, PDGFR, PI3K/Akt, and MAPKs in these responses were investigated by using the selective pharmacological inhibitors and transfection with siRNAs.ResultsHere, we demonstrate that JEV induces expression of pro-form MMP-9 via ROS/c-Src/PDGFR/PI3K/Akt/MAPKs-dependent, AP-1 activation in RBA-1 cells. JEV-induced MMP-9 expression and promoter activity were inhibited by pretreatment with inhibitors of AP-1 (tanshinone), c-Src (PP1), PDGFR (AG1296), and PI3K (LY294002), and by transfection with siRNAs of c-Jun, c-Fos, PDGFR, and Akt. Moreover, JEV-stimulated AP-1 activation was inhibited by pretreatment with the inhibitors of c-Src, PDGFR, PI3K, and MAPKs.ConclusionFrom these results, we conclude that JEV activates the ROS/c-Src/PDGFR/PI3K/Akt/MAPKs pathway, which in turn triggers AP-1 activation and ultimately induces MMP-9 expression in RBA-1 cells. These findings concerning JEV-induced MMP-9 expression in RBA-1 cells imply that JEV might play an important role in CNS inflammation and diseases.

Lipopolysaccharide induces ICAM-1 expression via a c-Src/NADPH oxidase/ROS-dependent NF-κB pathway in human pulmonary alveolar epithelial cells

“…5, E and G). NADPH oxidase/ROS generation has been shown to initiate EGFR or PDGFR activation in various cell types (17,31). Here, we showed that pretreatment with Edaravone, APO, or DPI or transfection with Nox2 or Nox4 siRNA markedly reduced LPS-stimulated EGFR and PDGFR phosphorylation in HPAEpiCs (Fig.…”

“…It has been reported that several G protein-coupled receptors initiate the PI3K/Akt pathway through transactivation of the EGFR or PDGFR in various cell types (3,16,31). However, little was known about the mechanisms of LPS that initiate the expression of ICAM-1 mediated through c-Src-dependent transactivation of EGFR or PDGFR in HPAEpiCs.…”

Correlation between negative expression of pepsinogen C and a series of phenotypic markers of gastric cancer in different gastric diseases

“…MMPs, a large family of calcium‐dependent zinc‐containing endopeptidases excreted as zymogens by a variety of cells including fibroblasts, macrophages, and neutrophils, play a critical role in tissue remodeling and degradation of extracellular matrix components 26. Previous studies have shown that MMP9 was closely correlated with inflammation, including Helicobacter pylori‐associated gastritis and encephalitis virus 27, 28. NM23, a metastasis suppressor protein, is associated with tumor metastasis, while its expression and prognostic value in GC is still controversial 29.…”

The West Nile Virus Capsid Protein Blocks Apoptosis through a Phosphatidylinositol 3-Kinase-Dependent Mechanism

“…As mentioned above, the kinetics of virus-induced survival signaling varies among cell lines and flaviviruses, and as a consequence, the extent of apoptosis is affected. With regard to WNV, Scherbik and Brinton (28) reported that infection of MEFs significantly increases phospho-Akt within 2 h of infection and this effect is sustained for more than 24 h. Similarly, JEV infection of RBA-1 cells activates the PI3K/Akt pathway, resulting in stimulatory phosphorylation of Akt within minutes (49). In contrast, WNV infection of neuro2A cells, a mouse neuroblastoma cell line, results in extensive cell death in less than 72 h, even at very low MOIs (50).…”

“…Specifically, several publications have shown that depending upon the specific flavivirus and cell type involved, PI3K/Akt signaling is activated within minutes (or hours) of infection with WNV, DENV, and JEV (26,27,49). Moreover, caspase-3 activation does not occur until later in infection, after the activation of PI3K/Akt has subsided.…”