Abstract
BackgroundNox-2 (also known as gp91phox), a subunit component of NADPH oxidases, generates reactive oxygen species (ROS). Nox-dependent ROS generation and nitric oxide (NO) release by microglia have been implicated in a variety of diseases in the central nervous system. Dexamethasone (Dex) has been shown to suppress the ROS production, NO release and inflammatory reaction of activated microglial cells. However, the underlying mechanisms remain unclear.ResultsThe present study showed that the increased ROS production and NO release in activated BV-2 microglial cells by LPS were associated with increased expression of Nox-2 and iNOS. Dex suppressed the upregulation of Nox-2 and iNOS, as well as the subsequent ROS production and NO synthesis in activated BV-2 cells. This inhibition caused by Dex appeared to be mediated by upregulation of MAPK phosphatase-1 (MKP-1), which antagonizes the activity of mitogen-activated protein kinases (MAPKs). Dex induced-suppression of Nox-2 and -upregulation of MKP-1 was also evident in the activated microglia from corpus callosum of postnatal rat brains. The overexpression of MKP-1 or inhibition of MAPKs (by specific inhibitors of JNK and p38 MAPKs), were found to downregulate the expression of Nox-2 and iNOS and thereby inhibit the synthesis of ROS and NO in activated BV-2 cells. Moreover, Dex was unable to suppress the LPS-induced synthesis of ROS and NO in BV-2 cells transfected with MKP-1 siRNA. On the other hand, knockdown of Nox-2 in BV-2 cells suppressed the LPS-induced ROS production and NO release.ConclusionIn conclusion, it is suggested that downregulation of Nox-2 and overexpression of MKP-1 that regulate ROS and NO may form the potential therapeutic strategy for the treatment of neuroinflammation in neurodegenerative diseases.
Highlights
Nox-2, a subunit component of Nicotinamide adenine dinuceotide phosphate (NADPH) oxidases, generates reactive oxygen species (ROS)
We have demonstrated that Dex suppresses microglia-involved inflammation by inhibiting production of monocyte chemoattractant protein-1 (MCP-1), a chemokine and subsequent migration of microglia via Mitogen activated protein kinase (MAPK) phosphatase-1 (MKP-1) dependent suppression of p38 and Jun N-terminal kinase (JNK) MAPK pathways in activated microglia [26]
LPS alters the ROS production and Nox-2 protein expression in BV-2 microglial cells in a dose- and timedependent manner ROS production in the BV-2 microglial cells treated with different concentrations of LPS (0.05, 0.1 and 0.3, 1, 1.5 μg/ml) was estimated in order to choose the optimum dose of LPS for further studies
Summary
Nox-2 ( known as gp91phox), a subunit component of NADPH oxidases, generates reactive oxygen species (ROS). Nox-dependent ROS generation and nitric oxide (NO) release by microglia have been implicated in a variety of diseases in the central nervous system. The chronic activation of these cells appears to cause neuronal damage through enhanced release of potentially cytotoxic molecules such as proinflammatory cytokines including tumor necrosis factor-a (TNF-a) and Nicotinamide adenine dinuceotide phosphate (NADPH) oxidase, a multi-component enzyme complex is an important source of reactive oxygen species (ROS) in respiratory oxidative stress and intracellular signaling pathways [8,9]. Nox-2 ( known as gp91phox), is expressed in the neuron and glial cells including microglia [10] and regulates NADPH oxidase activities by stabilizing p22phox ( a subunit of NADPH) to form its membrane component. Due to its expression in microglia and ability to generate large amounts of ROS, Nox protein is considered to be critical for ROS induction in activated microglia [10]
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