Ethanol selectively modulates inflammatory activation signaling of brain microglia

Lee, Heasuk; Jeong, Jaeyoon; Son, Eunyung; Mosa, Ahmed; Cho, Gyeong Jae; Choi, Wan Sung; Ha, Jeoung‐Hee; Kim, In Kyeom; Lee, Maan‐Gee; Kim, Choong-Young; Suk, Kyoungho

doi:10.1016/j.jneuroim.2004.07.008

Cited by 37 publications

(34 citation statements)

References 35 publications

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“…Acute ethanol treatment impairs the TLR-mediated macrophage inflammatory response, thus affecting both MAPK activation and cytokine production (32,33). Ethanol also inhibits LPS-induced IL-1␤ expression and NF-B activation in microglial cells (34). In contrast to these negative effects, activation of the LPS signaling response in Kupffer cells (35) and hepatocytes (20) appears to be involved in early alcohol-induced liver injury (36), and increased levels of proinflammatory cytokines are normally found in the serum of alcoholic patients with liver damage (37).…”

Section: Discussionmentioning

confidence: 99%

Involvement of TLR4/Type I IL-1 Receptor Signaling in the Induction of Inflammatory Mediators and Cell Death Induced by Ethanol in Cultured Astrocytes

Blanco

Vallés

Pascual

2005

The Journal of Immunology

234

220

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Activated astroglial cells are implicated in neuropathogenesis of many infectious and inflammatory diseases of the brain. A number of inflammatory mediators and cytokines have been proposed to play a key role in glial cell-related brain damage. Cytokine production seems to be initiated by signaling through TLR4/type I IL-1R (IL-1RI) in response to their ligands, LPS and IL-1β, playing vital roles in innate host defense against infections, inflammation, injury, and stress. We have shown that glial cells are stimulated by ethanol, up-regulating cytokines and inflammatory mediators associated with TLR4 and IL-1RI signaling pathways in brain, suggesting that ethanol may contribute to brain damage via inflammation. We explore the possibility that ethanol, in the absence of LPS or IL-1β, triggers signaling pathways and inflammatory mediators through TLR4 and/or IL-1RI activation in astrocytes. We show in this study that ethanol, at physiologically relevant concentrations, is capable of inducing rapid phosphorylation within 10 min of IL-1R-associated kinase, ERK1/2, stress-activated protein kinase/JNK, and p38 MAPK in astrocytes. Then an activation of NF-κB and AP-1 occurs after 30 min of ethanol treatment along with an up-regulation of inducible NO synthase and cyclooxygenase-2 expression. Finally, we note an increase in cell death after 3 h of treatment. Furthermore, by using either anti-TLR4- or anti-IL-1RI-neutralizing Abs, before and during ethanol treatment, we inhibit ethanol-induced signaling events, including NF-κB and AP-1 activation, inducible NO synthase, and cyclooxygenase-2 up-regulation and astrocyte death. In summary, these findings indicate that both TLR4 and IL-1RI activation occur upon ethanol treatment, and suggest that signaling through these receptors mediates ethanol-induced inflammatory events in astrocytes and brain.

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Section: Discussionmentioning

confidence: 99%

Involvement of TLR4/Type I IL-1 Receptor Signaling in the Induction of Inflammatory Mediators and Cell Death Induced by Ethanol in Cultured Astrocytes

Blanco

Vallés

Pascual

2005

The Journal of Immunology

234

220

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“…Monocytes isolated from the blood of alcoholics produce greater amounts of TNFα, a proinflammatory cytokine, spontaneously and in response to endotoxin challenge (McClain et al, 2004). The current study is designed to further investigate the roles of microglial recruitment and activation in alcohol induced inflammatory neurodegeneration (Lee et al, 2004;Crews et al, 2006;Pascual et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Increased MCP-1 and microglia in various regions of the human alcoholic brain

Crews

2008

Experimental Neurology

439

413

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Cytokines and microglia have been implicated in anxiety, depression, neurodegeneration as well as the regulation of alcohol drinking and other consumatory behaviors, all of which are associated with alcoholism. Studies using animal models of alcoholism suggest that microglia and proinflammatory cytokines contribute to alcoholic pathologies (Crews et al., 2006). In the current study, human postmortem brains from moderate drinking controls and alcoholics obtained from the New South Wales Tissue Resource Center were used to study the cytokine, monocyte chemoattractant protein 1 (MCP-1,CCL2) and microglia markers in various brain regions. Since MCP-1 is a key proinflammatory cytokine induced by chronic alcohol treatment of mice, and known to regulate drinking behavior in mice, MCP-1 protein levels from human brain homogenate were measured using ELISA, and indicated increased MCP-1 concentration in ventral tegmental area (VTA), substantia nigra (SN), hippocampus and amygdala of alcoholic brains as compared with controls. Immunohistochemistry was further performed to visualize human microglia using ionized calcium binding adaptor protein-1 (Iba-1), and Glucose transporter-5 (GluT 5 ). Alcoholics were found to have brain region-specific increases in microglial markers. In cingulate cortex, both Iba-1 and GluT 5 were increased in alcoholic brains relative to controls. Alternatively, no detectable change was found in amygdala nuclei. In VTA and midbrain, only GluT 5 , but not Iba-1 was increased in alcoholic brains. These data suggest that the enhanced expression of MCP-1 and microglia activities in alcoholic brains could contribute to ethanol-induced pathogenesis.

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“…In general, ethanol causes inhibition of cytokine-induced iNOS expression in a time-and concentration-dependent manner independent of cell or tissue type (Davis and Syapin, 2005). In the case of cultured glial cells, ethanol is effective at concentrations ranging from 25 mM to 200 mM (Lee, et al, 2004, Militante, et al, 1997, Syapin, et al, 2001, Wang and Sun, 2001, Wang, et al, 1998. The biological relevance of this concentration range is supported by results of both animal and human studies.…”

Section: Introductionmentioning

confidence: 93%

The Oct DNA motif participates in the alcohol inhibition of the inducible nitric oxide synthase gene promoter in rat C6 glioma cells

2007

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Induction of nitric-oxide synthase-2 (iNOS) by cytokines and bacterial products is associated with protein binding at the proximal promoter and in an upstream enhancer region of the Nos2 gene. To clarify how ethanol suppresses rat iNOS activity, we constructed several deletion mutants of the Nos2 promoter fused to the luciferase gene and transfected the constructs into C6 glial cells. Acute ethanol exposure of stably transfected cells for 24 h inhibits induced activity of Nos2 promoter constructs containing deletions in the 5′ flanking region, including a 94 bp promoter that lacks any known NF-κB site but which carries a C/EBPβ and overlapping γ-IRE, GAS and Oct motifs. Ethanol failed to inhibit the endogenous activity of a smaller, 78 bp promoter that lacks the C/EBPβ and overlapping, γ-IRE and GAS motifs and showed no inducible activity. As another approach, in vivo DNA footprinting was used and identified protein protections at five regions of the proximal Nos2 promoter in induced cells. Exposure to acute ethanol diminished protein occupation in the five promoter regions including the γ-IRE/NF-κB and the overlapping γIRE/GAS/Oct sites. Site-directed mutagenesis in the octamer domain of the γIRE/GAS/Oct motifs was studied in a 1002 bp promoter to examine its role in ethanol inhibition of cytokine and lipopolysaccharide induced activity. The data indicate ethanol failed to inhibit promoter activity when the Oct motif is missing. Electrophoretic mobility shift assays performed using a 22-mer probe containing the overlapping γ-IRE/GAS/Oct sites showed three complexes with one of the complexes being competed by an octamer-1 antibody. These observations demonstrate the role of protein-DNA binding at the core promoter, and the likely involvement of the octamer motif, in ethanol modulation of cytokine and lipopolysaccharide induced iNOS expression.

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Ethanol selectively modulates inflammatory activation signaling of brain microglia

Cited by 37 publications

References 35 publications

Involvement of TLR4/Type I IL-1 Receptor Signaling in the Induction of Inflammatory Mediators and Cell Death Induced by Ethanol in Cultured Astrocytes

Involvement of TLR4/Type I IL-1 Receptor Signaling in the Induction of Inflammatory Mediators and Cell Death Induced by Ethanol in Cultured Astrocytes

Increased MCP-1 and microglia in various regions of the human alcoholic brain

The Oct DNA motif participates in the alcohol inhibition of the inducible nitric oxide synthase gene promoter in rat C6 glioma cells

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