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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主要作者: Md Zain, Zuhaida
格式: Thesis
语言:English
出版: 2016
主题:
在线阅读:http://psasir.upm.edu.my/id/eprint/66821/1/FPSK%20%28m%29%202016%2073%20%20IR.pdf
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author Md Zain, Zuhaida
author_facet Md Zain, Zuhaida
author_sort Md Zain, Zuhaida
collection UPM
description 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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spelling upm.eprints-668212019-02-01T03:18:22Z http://psasir.upm.edu.my/id/eprint/66821/ Effects of GSK-3 inhibition on LPS-induced neuroinflammation and IL-10 production in microglia Md Zain, Zuhaida 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. 2016-09 Thesis NonPeerReviewed text en http://psasir.upm.edu.my/id/eprint/66821/1/FPSK%20%28m%29%202016%2073%20%20IR.pdf Md Zain, Zuhaida (2016) Effects of GSK-3 inhibition on LPS-induced neuroinflammation and IL-10 production in microglia. Masters thesis, Universiti Putra Malaysia. Glycogen Synthase Kinase 3 Microglia
spellingShingle Glycogen Synthase Kinase 3
Microglia
Md Zain, Zuhaida
Effects of GSK-3 inhibition on LPS-induced neuroinflammation and IL-10 production in microglia
title Effects of GSK-3 inhibition on LPS-induced neuroinflammation and IL-10 production in microglia
title_full Effects of GSK-3 inhibition on LPS-induced neuroinflammation and IL-10 production in microglia
title_fullStr Effects of GSK-3 inhibition on LPS-induced neuroinflammation and IL-10 production in microglia
title_full_unstemmed Effects of GSK-3 inhibition on LPS-induced neuroinflammation and IL-10 production in microglia
title_short Effects of GSK-3 inhibition on LPS-induced neuroinflammation and IL-10 production in microglia
title_sort effects of gsk 3 inhibition on lps induced neuroinflammation and il 10 production in microglia
topic Glycogen Synthase Kinase 3
Microglia
url http://psasir.upm.edu.my/id/eprint/66821/1/FPSK%20%28m%29%202016%2073%20%20IR.pdf
work_keys_str_mv AT mdzainzuhaida effectsofgsk3inhibitiononlpsinducedneuroinflammationandil10productioninmicroglia