Effects of GSK-3 inhibition on LPS-induced neuroinflammation and IL-10 production in microglia
Microglia are resident macrophages of the central nervous system (CNS) that play a role in the immune surveillance system against various pathogenicities. However, excessive inflammation resulting from activation of microglia has been implicated in the neurodegenerative diseases such as mult...
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| Main Author: | |
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| Format: | Thesis |
| Language: | English |
| Published: |
2016
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| Subjects: | |
| Online Access: | http://psasir.upm.edu.my/id/eprint/66821/1/FPSK%20%28m%29%202016%2073%20%20IR.pdf |
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| Summary: | Microglia are resident macrophages of the central nervous system (CNS) that
play a role in the immune surveillance system against various
pathogenicities. However, excessive inflammation resulting from activation of
microglia has been implicated in the neurodegenerative diseases such as
multiple sclerosis. The protein kinase, Glycogen Synthase Kinase (GSK) 3, is
involved in many cellular functions including microglial activation. Previously,
inhibition of GSK-3 has been shown to reduce inflammation due to
decreased production of pro-inflammatory cytokines and increased
production of IL-10 in LPS-induced endotoxin shock animal model. Thus, this
study was performed to elucidate the possible immunoregulatory effects of
GSK-3 inhibitors on activated microglia. We hypothesized that inhibition of
GSK-3 would reduce the exaggeration of inflammation in LPS-induced
microglial activation with associated increased of IL-10 production. The
optimal concentration of LPS and incubation period were optimized and
determined by measuring the level of nitric oxide (NO) produced by BV-2,
microglia cell lines, without compromising their effect on cell viability. The
GSK-3 inhibitors, including lithium chloride (LiCl), SB216763, NP12 and
CHIR99021 were used to block GSK-3 activities in the BV-2 cells. All GSK-3
inhibitors tested have shown their efficacy in reducing production of proinflammatory
molecules, such as NO, glutamate, MCP-1 and cytokines (TNF-
α and IL-6). Interestingly, reduction of pro-inflammatory molecules via GSK-3
inhibition was associated with significant increase in IL-10 production.
Furthermore, treatment with GSK-3 inhibitor reduced expression of microglial
activation markers, CD11b, while increased expressions of microglial
inhibitory markers, CD200R, which confirmed the ability of GSK-3 inhibitor in
inhibiting microglial activation. These results indicate that GSK-3 inhibitors
effectively reduced pro-inflammatory molecules via inhibition of microglial
activation. Moreover, these inhibitors could potentially reduce the severity of
neuroinflammation by enhancing IL-10 production. |
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