Increased systemic and brain cytokine production and neuroinflammation by endotoxin following ethanol treatment
Open accessAbstract
BACKGROUND: Cytokines and alcohol share a common modulation of inflammation and hormones as well as being implicated in multiple diseases, but the mechanisms are poorly understood. The purpose of this study was to investigate the interaction of liver, serum and brain cytokines as well as whether ethanol would potentiate endotoxin (Lipopolysaccharide, LPS) responses once ethanol had cleared. METHODS: Male C57BL/6J mice were treated intragastrically with water (control) or ethanol (5 g/kg, i.g., 25% ethanol, w/v), with volumes matched, for 1 day or daily for 10 days. Mice were then injected intraperitoneally with saline (control) or LPS (3 mg/kg, i.p.) in saline 24 hrs after the last dose of ethanol. Gene expression and protein synthesis of proinflammatory cytokines and anti-inflammatory cytokine, oxidative enzymes, microglial activation and inhibition of neurogenesis were examined using real-time PCR, ELISA, and immunohistochemistry. RESULTS: LPS increased proinflammatory cytokines (TNFalpha, MCP-1, IL-1beta) several fold in liver, brain and serum at 1 hr. Ethanol is known to increase liver cytokines and alter the risk of multiple chronic diseases. Ten daily doses of ethanol increased brain and liver TNFalpha, and pretreatment with ethanol potentiated LPS-induced increases in TNFalpha, MCP-1, IL-1beta in liver, serum and brain. Proinflammatory cytokine levels in liver and serum returned to basal levels within a day, whereas brain proinflammatory cytokines remained elevated for long periods. IL-10, an anti-inflammatory cytokine, is reduced in brain by ethanol and LPS, while brain proinflammatory cytokines remain increased, whereas liver IL-10 is increased when proinflammatory cytokines have returned to control levels. Activation of brain microglia indicated by morphological changes, reduced neurogenesis and increased brain expression of COX-2 and gp91phox NADPH oxidase subunit mRNA were found in the 10 daily doses of ethanol-pretreated LPS group. CONCLUSION: Acute increases in serum cytokines induce long lasting increases in brain proinflammatory cytokines. Ten daily doses of ethanol exposure results in persistent alterations of cytokines and significantly increases the magnitude and duration of central and peripheral proinflammatory cytokines and microglial activation. Ethanol induced differential anti-inflammatory cytokine IL-10 responses in liver and brain could cause long lasting disruption of cytokine cascades that could contribute to protection or increased risk of multiple chronic diseases.
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Increased circulation of BBB-permeable pro-inflammatory cytokines and neurotoxic compounds may contribute to heightened microglial activation and production of pro-inflammatory cytokines in the brain.
“Increased circulation of BBB-permeable pro-inflammatory cytokines and neurotoxic compounds may contribute to heightened microglial activation and production of pro-inflammatory cytokines in the brain (Qin et al., 2008; Riazi et al., 2008).”
From Microbiome–microglia connections via the gut–brain axis (2019) · cites this paper as Qin et al., 2008
Animal studies find alcohol-induced proinflammatory gene expression with neurodegeneration.
“Animal studies find alcohol induced proinflammatory gene expression with neurodegeneration (Crews et al., 2006a; Qin et al., 2008).”
From Impulsivity, frontal lobes and risk for addiction (2009) · cites this paper as Qin et al., 2008
Chronic alcohol exposure increases brain levels of inflammatory mediators such as IL-1.
“increases brain levels of inflammatory mediators such as IL-1 (Qin et al., 2008)”
From Stress- and Glucocorticoid-Induced Priming of Neuroinflammatory Responses: Potential Mechanisms of Stress-Induced Vulnerability to Drugs of Abuse (2011) · cites this paper as Qin et al., 2008
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Cites
Inflammatory Blockade Restores Adult Hippocampal Neurogenesis
Monje, M. L., Toda, H., & Palmer, T. D. (2003) · Science · doi:10.1126/science.1088417 · Cited by 2,426 · see citing works
Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration
Qin, L., Wu, X., Block, M. L., Liu, Y., Breese, G. R., Hong, J., Knapp, D. J., & Crews, F. T. (2007) · Glia · doi:10.1002/glia.20467 · Cited by 2,144 · see citing works
Self-citationGu, L., Okada, Y., Clinton, S. K., Gerard, C. J., Sukhova, G. K., Libby, P., & Rollins, B. J. (1998) · Molecular Cell · doi:10.1016/s1097-2765(00)80139-2 · Cited by 1,574 · see citing works
Interleukin (IL)-10 Inhibits Nuclear Factor кB (NFкB) Activation in Human Monocytes
Wang, P., Wu, P., Siegel, M. I., Egan, R. W., & Billah, M. M. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.16.9558 · Cited by 700 · see citing works
Qin, L., Liu, Y., Wang, T., Wei, S.-J., Block, M. L., Wilson, B., Liu, B., & Hong, J.-S. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m307657200 · Cited by 574 · see citing works
Self-citationIncreased tumor necrosis factor production by monocytes in alcoholic hepatitis
McClain, C. J., & Cohen, D. A. (1989) · Hepatology · doi:10.1002/hep.1840090302 · Cited by 540 · see citing works
Blood-brain barrier transport of cytokines: a mechanism for neuropathology
Banks, W. (2005) · Current Pharmaceutical Design · doi:10.2174/1381612053381684 · Cited by 534 · see citing works
Increased MCP-1 and microglia in various regions of the human alcoholic brain
He, J., & Crews, F. T. (2007) · Experimental Neurology · doi:10.1016/j.expneurol.2007.11.017 · Cited by 516 · see citing works
Self-citationSelection of reference genes for gene expression studies in pig tissues using SYBR green qPCR
Nygård, A.-B., Jørgensen, C. B., Cirera, S., & Fredholm, M. (2007) · BMC Molecular Biology · doi:10.1186/1471-2199-8-67 · Cited by 505 · see citing works
Binge ethanol exposure decreases neurogenesis in adult rat hippocampus
Nixon, K., & Crews, F. T. (2002) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2002.01214.x · Cited by 480 · see citing works
Self-citationImpact of alcohol on the histological and clinical progression of Hepatitis C infection
Wiley, T. E., McCarthy, M., Breidi, L., McCarthy, M., & Layden, T. J. (1998) · Hepatology · doi:10.1002/hep.510280330 · Cited by 434 · see citing works
Crews, F. T., Bechara, R. I., Brown, L. A. S., Guidot, D. M., Mandrekar, P., Oak, S. A., Qin, L., Szabó, G., Wheeler, M. D., & Zou, J. (2006) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.2006.00084.x · Cited by 414 · see citing works
Self-citationCytokines in Alcoholic Liver Disease
McClain, C. J., Barve, S. S., Deaciuc, I. V., Kugelmas, M., & Hill, D. B. (1999) · Seminars in Liver Disease · doi:10.1055/s-2007-1007110 · Cited by 399 · see citing works
IL-10 inhibits transcription of cytokine genes in human peripheral blood mononuclear cells.
Wang, P., Wu, P., Siegel, M. I., Egan, R. W., & Billah, M. M. (1994) · The Journal of Immunology · doi:10.4049/jimmunol.153.2.811 · Cited by 329 · see citing works
Interleukin-1 and inflammatory neurodegeneration
Simi, A., Tsakiri, N., Wang, P., & Rothwell, N. J. (2007) · Biochemical Society Transactions · doi:10.1042/bst0351122 · Cited by 286 · see citing works
Alcohol, host defence and society
Nelson, S., & Kolls, J. K. (2002) · Nature reviews. Immunology · doi:10.1038/nri744 · Cited by 268 · see citing works
McClain, C. J., Song, Z., Barve, S. S., Hill, D. B., & Deaciuc, I. V. (2004) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00171.2004 · Cited by 254 · see citing works
TNFα Transport across the Blood–Brain Barrier Is Abolished in Receptor Knockout Mice
Pan, W., & Kastin, A. J. (2002) · Experimental Neurology · doi:10.1006/exnr.2002.7871 · Cited by 210 · see citing works
Who drinks most of the alcohol in the US? The policy implications.
Greenfield, T. K., & Rogers, J. (1999) · Journal of Studies on Alcohol · doi:10.15288/jsa.1999.60.78 · Cited by 174 · see citing works
Carson, E. J., & Pruett, S. B. (1996) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.1996.tb01055.x · Cited by 167 · see citing works
Liu, Y., Lin, H.-I., & Tzeng, S. (2005) · Brain Research · doi:10.1016/j.brainres.2005.06.085 · Cited by 130 · see citing works
Enomoto, N., Takei, Y., Hirose, M., Konno, A., Shibuya, T., Matsuyama, S., Suzuki, S., Ikejima, K., & Sato, N. (2003) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.102.047217 · Cited by 99 · see citing works
Neuroprotective Strategies in Parkinson's Disease Using the Models of 6‐Hydroxydopamine and MPTPa
Grünblatt, E., Mandel, S. A., & Youdim, M. B. H. (2000) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2000.tb06192.x · Cited by 91 · see citing works
Pathogenesis of Parkinson's Disease: Prospects of Neuroprotective and Restorative Therapies
Fernández‐Espejo, E. (2004) · Molecular Neurobiology · doi:10.1385/mn:29:1:15 · Cited by 88 · see citing works
Iwai, M., Cui, T., Kitamura, H., Saito, M., & Shimazu, T. (2001) · Cytokine · doi:10.1006/cyto.2000.0797 · Cited by 77 · see citing works
Alcohol modulates cytokine secretion and synthesis in human fetus: an in vivo and in vitro study
Ahluwalia, B. S., Wesley, B. D., Adeyiga, O., et al. (2000) · Alcohol · doi:10.1016/s0741-8329(00)00076-8 · Cited by 70 · see citing works
Zhang, P., Nelson, S., Summer, W. R., & Spitzer, J. A. (1997) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.1997.tb03838.x · Cited by 62 · see citing works
CHRONIC ALCOHOLISM CAUSES DELETERIOUS CONDITIONING OF INNATE IMMUNITY
Frank, J., Witte, K., Schrödl, W., & Schütt, C. (2004) · Alcohol and Alcoholism · doi:10.1093/alcalc/agh083 · Cited by 47 · see citing works
Kiefer, F. (2002) · Alcohol and Alcoholism · doi:10.1093/alcalc/37.4.401 · Cited by 44 · see citing works
An explanation for the paradoxical induction and suppression of an acute phase response by ethanol
Pruett, B. S., & Pruett, S. B. (2006) · Alcohol · doi:10.1016/j.alcohol.2006.08.003 · Cited by 43 · see citing works
Chechneva, O. V., Dinkel, K., Cavaliere, F., Martínez‐Sánchez, M., & Reymann, K. G. (2006) · Neurobiology of Disease · doi:10.1016/j.nbd.2006.02.015 · Cited by 37 · see citing works
Zuo, G. (2001) · World Journal of Gastroenterology · doi:10.3748/wjg.v7.i6.836 · Cited by 21 · see citing works
Emanuele, N., LaPaglia, N., Kovacs, E. J., & Emanuele, M. A. (2005) · Endocrine Research · doi:10.1080/07435800500228930 · Cited by 17 · see citing works
Prakash, O., Zhang, P., Xie, M., et al. (1998) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.1998.tb05914.x · Cited by 16 · see citing works
The Role of Kupffer Cells After Major Liver Surgery
Prins, H. A., Meijer, C., Boelens, P. G., et al. (2005) · Journal of Parenteral and Enteral Nutrition · doi:10.1177/014860710502900148 · Cited by 3 · see citing works
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Self-citationPivotal role of TLR4 receptors in alcohol-induced neuroinflammation and brain damage
Alfonso-Loeches, S., Pascual-Lucas, M., Blanco, A. M., Sanchez-Vera, I., & Guerri, C. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.0976-10.2010 · Cited by 579 · see citing works
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- Authors
- Qin, L., He, J., Hanes, R. N., Pluzarev, O., Hong, J.-S., & Crews, F. T.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- National Institute of Environmental Health Sciences (US)
- Corresponding author
- Crews, Fulton T
- Venue
- Journal of Neuroinflammation
- Published
- 2008-03-18
- Volume
- 5
- Issue
- 1
- Pages
- 10-10
- ISSN
- 1742-2094 (ISSN-L)
- PMC
- PMC2373291
- OpenAlex
- W2009962309
- Cited by
- 532
- References
- 35
- Citations by year
- 2026: 11 · 2025: 21 · 2024: 28 · 2023: 36 · 2022: 31 · 2021: 44 · 2020: 30 · 2019: 35 · 2018: 37 · 2017: 41 · 2016: 31 · 2015: 30 · 2014: 28 · 2013: 28 · 2012: 43
- FWCI
- 13.72
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Journal of Neuroinflammation (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion, cc-by)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UNC Libraries
- Funders
- National Institute on Alcohol Abuse and Alcoholism
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- ethanol, endotoxin, lipopolysaccharide, inflammatory cytokines, neuroinflammation, IL-10, microglial activation, neurogenesis, TNF-α, MCP-1, IL-1β, cyclooxygenase-2, NADPH oxidase, oxidative stress, brain cytokines
- MeSH terms
- NADPH Oxidase 2, Ethanol, Animals, Brain, Central Nervous System Depressants, Dose-Response Relationship, Drug, Encephalitis, Endotoxins, Lipopolysaccharides, Liver, Male, Membrane Glycoproteins, Mice, Inbred C57BL, Random Allocation, Tumor Necrosis Factor-alpha, Cytokines, Interleukin-10, Chemokine CCL2, NADPH Oxidases, Mice, Cyclooxygenase 2, Interleukin-1beta
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