Ethanol and Cytokines in the Central Nervous System

  • Marisa RobertoEmail author
  • Reesha R. Patel
  • Michal Bajo
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 248)


The innate immune system plays a critical role in the ethanol-induced neuroimmune response in the brain. Ethanol initiates the innate immune response via activation of the innate immune receptors Toll-like receptors (TLRs, e.g., TLR4, TLR3, TLR7) and NOD-like receptors (inflammasome NLRs) leading to a release of a plethora of chemokines and cytokines and development of the innate immune response. Cytokines and chemokines can have pro- or anti-inflammatory properties through which they regulate the immune response. In this chapter, we will focus on key cytokines (e.g., IL-1, IL-6, TNF-α) and chemokines (e.g., MCP-1/CCL2) that mediate the ethanol-induced neuroimmune responses. In this regard, we will use IL-1β, as an example cytokine, to discuss the neuromodulatory properties of cytokines on cellular properties and synaptic transmission. We will discuss their involvement through a set of evidence: (1) changes in gene and protein expression following ethanol exposure, (2) association of gene polymorphisms (humans) and alterations in gene expression (animal models) with increased alcohol intake, and (3) modulation of alcohol-related behaviors by transgenic or pharmacological manipulations of chemokine and cytokine systems. Over the last years, our understanding of the molecular mechanisms mediating cytokine- and chemokine-dependent regulation of immune responses has advanced tremendously, and we review evidence pointing to cytokines and chemokines serving as neuromodulators and regulators of neurotransmission.


Alcohol Inflammatory mediators Neuroimmune system Synaptic transmission 



This publication was supported by National Institutes of Health grants U01 AA013498, AA015566, AA006420, AA017447, T32 AA007456, and R01 AA021491 from the National Institute on Alcohol Abuse and Alcoholism and the Pearson Center for Alcoholism and Addiction Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.


  1. Abbas AK et al (2018) Cellular and molecular immunology. Elsevier, AmsterdamGoogle Scholar
  2. Ahlers KE et al (2015) Transient activation of microglia following acute alcohol exposure in developing mouse neocortex is primarily driven by BAX-dependent neurodegeneration. Glia 63(10):1694–1713PubMedPubMedCentralGoogle Scholar
  3. Alfonso-Loeches S, Pascual M, Guerri C (2013) Gender differences in alcohol-induced neurotoxicity and brain damage. Toxicology 311(1–2):27–34PubMedGoogle Scholar
  4. Alfonso-Loeches S et al (2014) Role of mitochondria ROS generation in ethanol-induced NLRP3 inflammasome activation and cell death in astroglial cells. Front Cell Neurosci 8:216PubMedPubMedCentralGoogle Scholar
  5. Alfonso-Loeches S et al (2015) Ethanol-induced TLR4/NLRP3 neuroinflammatory response in microglial cells promotes leukocyte infiltration across the BBB. Neurochem Res 41(1–2):193–209PubMedGoogle Scholar
  6. Allan SM, Tyrrell PJ, Rothwell NJ (2005) Interleukin-1 and neuronal injury. Nat Rev Immunol 5(8):629–640PubMedGoogle Scholar
  7. Amin FU, Shah SA, Kim MO (2016) Glycine inhibits ethanol-induced oxidative stress, neuroinflammation and apoptotic neurodegeneration in postnatal rat brain. Neurochem Int 96:1–12PubMedGoogle Scholar
  8. Andjelkovic AV et al (2002) Functional expression of CCR2 by human fetal astrocytes. J Neurosci Res 70(2):219–231PubMedGoogle Scholar
  9. Annunziata P et al (2002) Substance P antagonist blocks leakage and reduces activation of cytokine-stimulated rat brain endothelium. J Neuroimmunol 131(1–2):41–49PubMedGoogle Scholar
  10. Apartis E et al (2010) Chemokines as new actors in the dopaminergic system. Biol Aujourdhui 204(4):295–300PubMedGoogle Scholar
  11. Bachelerie F et al (2014) International Union of Basic and Clinical Pharmacology. [corrected]. LXXXIX. Update on the extended family of chemokine receptors and introducing a new nomenclature for atypical chemokine receptors. Pharmacol Rev 66(1):1–79PubMedPubMedCentralGoogle Scholar
  12. Bajo M et al (2014) Innate immune factors modulate ethanol interaction with GABAergic transmission in mouse central amygdala. Brain Behav Immun 40:191–202PubMedPubMedCentralGoogle Scholar
  13. Bajo M et al (2015a) Role of the IL-1 receptor antagonist in ethanol-induced regulation of GABAergic transmission in the central amygdala. Brain Behav Immun 45:189–197PubMedGoogle Scholar
  14. Bajo M et al (2015b) IL-1 interacts with ethanol effects on GABAergic transmission in the mouse central amygdala. Front Pharmacol 6:49PubMedPubMedCentralGoogle Scholar
  15. Banisadr G et al (2005a) Highly regionalized neuronal expression of monocyte chemoattractant protein-1 (MCP-1/CCL2) in rat brain: evidence for its colocalization with neurotransmitters and neuropeptides. J Comp Neurol 489(3):275–292PubMedGoogle Scholar
  16. Banisadr G et al (2005b) Constitutive neuronal expression of CCR2 chemokine receptor and its colocalization with neurotransmitters in normal rat brain: functional effect of MCP-1/CCL2 on calcium mobilization in primary cultured neurons. J Comp Neurol 492(2):178–192PubMedGoogle Scholar
  17. Banks WA (2015) The blood-brain barrier in neuroimmunology: tales of separation and assimilation. Brain Behav Immun 44:1–8PubMedGoogle Scholar
  18. Bardou I et al (2014) Age and duration of inflammatory environment differentially affect the neuroimmune response and catecholaminergic neurons in the midbrain and brainstem. Neurobiol Aging 35(5):1065–1073PubMedGoogle Scholar
  19. Barker BR, Taxman DJ, Ting JP (2011) Cross-regulation between the IL-1beta/IL-18 processing inflammasome and other inflammatory cytokines. Curr Opin Immunol 23(5):591–597PubMedPubMedCentralGoogle Scholar
  20. Beattie MS et al (2002) Cell death in models of spinal cord injury. Prog Brain Res 137:37–47PubMedGoogle Scholar
  21. Becher B, Spath S, Goverman J (2017) Cytokine networks in neuroinflammation. Nat Rev Immunol 17(1):49–59PubMedGoogle Scholar
  22. Bell RL et al (2015) Ibudilast reduces alcohol drinking in multiple animal models of alcohol dependence. Addict Biol 20(1):38–42PubMedGoogle Scholar
  23. Bezzi P et al (2001) Neuron-astrocyte cross-talk during synaptic transmission: physiological and neuropathological implications. Prog Brain Res 132:255–265PubMedGoogle Scholar
  24. Biswas SK, Lopez-Collazo E (2009) Endotoxin tolerance: new mechanisms, molecules and clinical significance. Trends Immunol 30(10):475–487PubMedGoogle Scholar
  25. Blanco AM, Guerri C (2007) Ethanol intake enhances inflammatory mediators in brain: role of glial cells and TLR4/IL-1RI receptors. Front Biosci 12:2616–2630PubMedGoogle Scholar
  26. Blanco AM et al (2005) Involvement of TLR4/type I IL-1 receptor signaling in the induction of inflammatory mediators and cell death induced by ethanol in cultured astrocytes. J Immunol 175(10):6893–6899PubMedGoogle Scholar
  27. Blednov YA et al (2003) Deletion of the alpha1 or beta2 subunit of GABAA receptors reduces actions of alcohol and other drugs. J Pharmacol Exp Ther 304(1):30–36PubMedGoogle Scholar
  28. Blednov YA et al (2005) Perturbation of chemokine networks by gene deletion alters the reinforcing actions of ethanol. Behav Brain Res 165(1):110–125PubMedPubMedCentralGoogle Scholar
  29. Blednov YA et al (2011) Loss of ethanol conditioned taste aversion and motor stimulation in knockin mice with ethanol-insensitive alpha2-containing GABA(A) receptors. J Pharmacol Exp Ther 336(1):145–154PubMedPubMedCentralGoogle Scholar
  30. Blednov YA et al (2012) Neuroimmune regulation of alcohol consumption: behavioral validation of genes obtained from genomic studies. Addict Biol 17(1):108–120PubMedGoogle Scholar
  31. Blednov YA et al (2013) Linking GABA(A) receptor subunits to alcohol-induced conditioned taste aversion and recovery from acute alcohol intoxication. Neuropharmacology 67:46–56PubMedGoogle Scholar
  32. Blednov YA et al (2014) Inhibition of phosphodiesterase 4 reduces ethanol intake and preference in C57BL/6J mice. Front Neurosci 8:129PubMedPubMedCentralGoogle Scholar
  33. Blednov YA et al (2015a) Role of interleukin-1 receptor signaling in the behavioral effects of ethanol and benzodiazepines. Neuropharmacology 95:309–320PubMedPubMedCentralGoogle Scholar
  34. Blednov YA et al (2015b) Peroxisome proliferator-activated receptors alpha and gamma are linked with alcohol consumption in mice and withdrawal and dependence in humans. Alcohol Clin Exp Res 39(1):136–145PubMedGoogle Scholar
  35. Boddeke EW et al (1999) Cultured rat microglia express functional beta-chemokine receptors. J Neuroimmunol 98(2):176–184PubMedGoogle Scholar
  36. Boehm SL 2nd et al (2004) gamma-Aminobutyric acid A receptor subunit mutant mice: new perspectives on alcohol actions. Biochem Pharmacol 68(8):1581–1602PubMedGoogle Scholar
  37. Boulanger LM (2009) Immune proteins in brain development and synaptic plasticity. Neuron 64(1):93–109PubMedGoogle Scholar
  38. Boyadjieva NI, Sarkar DK (2010) Role of microglia in ethanol’s apoptotic action on hypothalamic neuronal cells in primary cultures. Alcohol Clin Exp Res 34(11):1835–1842PubMedPubMedCentralGoogle Scholar
  39. Brambilla D et al (2007) Interleukin-1 inhibits firing of serotonergic neurons in the dorsal raphe nucleus and enhances GABAergic inhibitory post-synaptic potentials. Eur J Neurosci 26(7):1862–1869PubMedGoogle Scholar
  40. Bray JG et al (2013) Synaptic plasticity in the hippocampus shows resistance to acute ethanol exposure in transgenic mice with astrocyte-targeted enhanced CCL2 expression. Neuropharmacology 67:115–125PubMedGoogle Scholar
  41. Breese GR et al (2008) Repeated lipopolysaccharide (LPS) or cytokine treatments sensitize ethanol withdrawal-induced anxiety-like behavior. Neuropsychopharmacology 33(4):867–876PubMedGoogle Scholar
  42. Callahan MK, Ransohoff RM (2004) Analysis of leukocyte extravasation across the blood-brain barrier: conceptual and technical aspects. Curr Allergy Asthma Rep 4(1):65–73PubMedGoogle Scholar
  43. Cartmell T, Luheshi GN, Rothwell NJ (1999) Brain sites of action of endogenous interleukin-1 in the febrile response to localized inflammation in the rat. J Physiol 518(Pt 2):585–594PubMedPubMedCentralGoogle Scholar
  44. Chai Z et al (1996) Interleukin (IL)-6 gene expression in the central nervous system is necessary for fever response to lipopolysaccharide or IL-1 beta: a study on IL-6-deficient mice. J Exp Med 183(1):311–316PubMedGoogle Scholar
  45. Chang GQ, Karatayev O, Leibowitz SF (2015) Prenatal exposure to ethanol stimulates hypothalamic CCR2 chemokine receptor system: possible relation to increased density of orexigenic peptide neurons and ethanol drinking in adolescent offspring. Neuroscience 310:163–175PubMedPubMedCentralGoogle Scholar
  46. Chaturvedi LS, Zhang P, Basson MD (2012) Effects of extracellular pressure and alcohol on the microglial response to inflammatory stimulation. Am J Surg 204(5):602–606PubMedGoogle Scholar
  47. Choi SS et al (2014) Human astrocytes: secretome profiles of cytokines and chemokines. PLoS One 9(4):e92325PubMedPubMedCentralGoogle Scholar
  48. Cohen P (2014) The TLR and IL-1 signalling network at a glance. J Cell Sci 127(Pt 11):2383–2390PubMedPubMedCentralGoogle Scholar
  49. Conductier G et al (2010) The role of monocyte chemoattractant protein MCP1/CCL2 in neuroinflammatory diseases. J Neuroimmunol 224(1–2):93–100PubMedGoogle Scholar
  50. Conroy SM et al (2004) Interleukin-6 produces neuronal loss in developing cerebellar granule neuron cultures. J Neuroimmunol 155(1–2):43–54PubMedGoogle Scholar
  51. Crews FT, Vetreno RP (2014) Neuroimmune basis of alcoholic brain damage. Int Rev Neurobiol 118:315–357PubMedPubMedCentralGoogle Scholar
  52. Crews FT et al (2017) The role of neuroimmune signaling in alcoholism. Neuropharmacology 122:56–73PubMedPubMedCentralGoogle Scholar
  53. Curtale G et al (2013) Negative regulation of toll-like receptor 4 signaling by IL-10-dependent microRNA-146b. Proc Natl Acad Sci U S A 110(28):11499–11504PubMedPubMedCentralGoogle Scholar
  54. Dansereau MA et al (2008) Spinal CCL2 pronociceptive action is no longer effective in CCR2 receptor antagonist-treated rats. J Neurochem 106(2):757–769PubMedGoogle Scholar
  55. Davis M, Rainnie D, Cassell M (1994) Neurotransmission in the rat amygdala related to fear and anxiety. Trends Neurosci 17(5):208–214PubMedGoogle Scholar
  56. Dawson J et al (2003) Targeting monocyte chemoattractant protein-1 signalling in disease. Expert Opin Ther Targets 7(1):35–48PubMedGoogle Scholar
  57. Dayas CV et al (2001) Stressor categorization: acute physical and psychological stressors elicit distinctive recruitment patterns in the amygdala and in medullary noradrenergic cell groups. Eur J Neurosci 14(7):1143–1152PubMedGoogle Scholar
  58. Dennis CV et al (2014) Microglial proliferation in the brain of chronic alcoholics with hepatic encephalopathy. Metab Brain Dis 29(4):1027–1039PubMedGoogle Scholar
  59. Diaz A et al (2016) Energy drink administration in combination with alcohol causes an inflammatory response and oxidative stress in the hippocampus and temporal cortex of rats. Oxidative Med Cell Longev 2016:8725354Google Scholar
  60. Dimitrov S et al (2006) Sleep enhances IL-6 trans-signaling in humans. FASEB J 20(12):2174–2176PubMedGoogle Scholar
  61. Dinarello CA (2011) Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood 117(14):3720–3732PubMedPubMedCentralGoogle Scholar
  62. Doremus-Fitzwater TL et al (2014) Intoxication- and withdrawal-dependent expression of central and peripheral cytokines following initial ethanol exposure. Alcohol Clin Exp Res 38:2186–2198PubMedPubMedCentralGoogle Scholar
  63. Doremus-Fitzwater TL et al (2015) Male adolescent rats display blunted cytokine responses in the CNS after acute ethanol or lipopolysaccharide exposure. Physiol Behav 148:131–144PubMedPubMedCentralGoogle Scholar
  64. Drew PD et al (2015) Pioglitazone blocks ethanol induction of microglial activation and immune responses in the hippocampus, cerebellum, and cerebral cortex in a mouse model of fetal alcohol spectrum disorders. Alcohol Clin Exp Res 39(3):445–454PubMedPubMedCentralGoogle Scholar
  65. Du L et al (2017) Role of microglia in neurological disorders and their potentials as a therapeutic target. Mol Neurobiol 54(10):7567–7584PubMedGoogle Scholar
  66. Dunn AJ, Wang J, Ando T (1999) Effects of cytokines on cerebral neurotransmission. Comparison with the effects of stress. Adv Exp Med Biol 461:117–127PubMedGoogle Scholar
  67. Emanuele N et al (2005) Effects of chronic ethanol (EtOH) administration on pro-inflammatory cytokines of the hypothalamic-pituitary-gonadal (HPG) axis in female rats. Endocr Res 31(1):9–16PubMedGoogle Scholar
  68. Erickson MA, Banks WA (2011) Cytokine and chemokine responses in serum and brain after single and repeated injections of lipopolysaccharide: multiplex quantification with path analysis. Brain Behav Immun 25(8):1637–1648PubMedPubMedCentralGoogle Scholar
  69. Erickson MA, Dohi K, Banks WA (2012) Neuroinflammation: a common pathway in CNS diseases as mediated at the blood-brain barrier. Neuroimmunomodulation 19(2):121–130PubMedPubMedCentralGoogle Scholar
  70. Ericsson A et al (1995) Type 1 interleukin-1 receptor in the rat brain: distribution, regulation, and relationship to sites of IL-1-induced cellular activation. J Comp Neurol 361(4):681–698PubMedGoogle Scholar
  71. Eriksson C et al (2000) Increased expression of mRNA encoding interleukin-1beta and caspase-1, and the secreted isoform of interleukin-1 receptor antagonist in the rat brain following systemic kainic acid administration. J Neurosci Res 60(2):266–279PubMedGoogle Scholar
  72. Erta M, Quintana A, Hidalgo J (2012) Interleukin-6, a major cytokine in the central nervous system. Int J Biol Sci 8(9):1254–1266PubMedPubMedCentralGoogle Scholar
  73. Farina C, Aloisi F, Meinl E (2007) Astrocytes are active players in cerebral innate immunity. Trends Immunol 28(3):138–145PubMedGoogle Scholar
  74. Fattori E et al (1995) IL-6 expression in neurons of transgenic mice causes reactive astrocytosis and increase in ramified microglial cells but no neuronal damage. Eur J Neurosci 7(12):2441–2449PubMedGoogle Scholar
  75. Feleder C et al (1998) Interleukin-1 stimulates hypothalamic inhibitory amino acid neurotransmitter release. Neuroimmunomodulation 5(1–2):1–4PubMedGoogle Scholar
  76. Ferguson AR et al (2008) Cell death after spinal cord injury is exacerbated by rapid TNF alpha-induced trafficking of GluR2-lacking AMPARs to the plasma membrane. J Neurosci 28(44):11391–11400PubMedPubMedCentralGoogle Scholar
  77. Fickenscher H et al (2002) The interleukin-10 family of cytokines. Trends Immunol 23(2):89–96PubMedGoogle Scholar
  78. Freeman K et al (2012) Temporal changes in innate immune signals in a rat model of alcohol withdrawal in emotional and cardiorespiratory homeostatic nuclei. J Neuroinflammation 9:97PubMedPubMedCentralGoogle Scholar
  79. French RA et al (1999) Expression and localization of p80 and p68 interleukin-1 receptor proteins in the brain of adult mice. J Neuroimmunol 93(1–2):194–202PubMedGoogle Scholar
  80. Frost P et al (2001) IL-1 receptor type I gene expression in the amygdala of inflammatory susceptible Lewis and inflammatory resistant Fischer rats. J Neuroimmunol 121(1–2):32–39PubMedGoogle Scholar
  81. Gano A et al (2017) Conditioned effects of ethanol on the immune system. Exp Biol Med (Maywood) 242(7):718–730Google Scholar
  82. Garcia-Oscos F et al (2012) The stress-induced cytokine interleukin-6 decreases the inhibition/excitation ratio in the rat temporal cortex via trans-signaling. Biol Psychiatry 71(7):574–582PubMedGoogle Scholar
  83. Gardoni F et al (2011) Distribution of interleukin-1 receptor complex at the synaptic membrane driven by interleukin-1beta and NMDA stimulation. J Neuroinflammation 8(1):14PubMedPubMedCentralGoogle Scholar
  84. Garlanda C, Dinarello CA, Mantovani A (2013) The interleukin-1 family: back to the future. Immunity 39(6):1003–1018PubMedPubMedCentralGoogle Scholar
  85. Gayle D et al (1999) Basal and IL-1beta-stimulated cytokine and neuropeptide mRNA expression in brain regions of young and old Long-Evans rats. Brain Res Mol Brain Res 70(1):92–100PubMedGoogle Scholar
  86. Geil CR et al (2014) Alcohol and adult hippocampal neurogenesis: promiscuous drug, wanton effects. Prog Neuro-Psychopharmacol Biol Psychiatry 54:103–113Google Scholar
  87. Gitter BD et al (1994) Interleukin-6 secretion from human astrocytoma cells induced by substance P. J Neuroimmunol 51(1):101–108PubMedGoogle Scholar
  88. Goshen I et al (2007) A dual role for interleukin-1 in hippocampal-dependent memory processes. Psychoneuroendocrinology 32(8–10):1106–1115PubMedGoogle Scholar
  89. Gottesfeld Z, Moore AN, Dash PK (2002) Acute ethanol intake attenuates inflammatory cytokines after brain injury in rats: a possible role for corticosterone. J Neurotrauma 19(3):317–326PubMedGoogle Scholar
  90. Grell M et al (1995) The transmembrane form of tumor necrosis factor is the prime activating ligand of the 80 kDa tumor necrosis factor receptor. Cell 83(5):793–802PubMedGoogle Scholar
  91. Gruol DL (2016) Impact of increased astrocyte expression of IL-6, CCL2 or CXCL10 in transgenic mice on hippocampal synaptic function. Brain Sci 6(2).
  92. Guyon A et al (2009) Long term exposure to the chemokine CCL2 activates the nigrostriatal dopamine system: a novel mechanism for the control of dopamine release. Neuroscience 162(4):1072–1080PubMedGoogle Scholar
  93. Hagan P, Poole S, Bristow AF (1993) Endotoxin-stimulated production of rat hypothalamic interleukin-1 beta in vivo and in vitro, measured by specific immunoradiometric assay. J Mol Endocrinol 11(1):31–36PubMedGoogle Scholar
  94. He J, Crews FT (2008) Increased MCP-1 and microglia in various regions of the human alcoholic brain. Exp Neurol 210(2):349–358PubMedGoogle Scholar
  95. He P et al (2012) Genetic deletion of TNF receptor suppresses excitatory synaptic transmission via reducing AMPA receptor synaptic localization in cortical neurons. FASEB J 26(1):334–345PubMedPubMedCentralGoogle Scholar
  96. Heida JG, Pittman QJ (2005) Causal links between brain cytokines and experimental febrile convulsions in the rat. Epilepsia 46(12):1906–1913PubMedGoogle Scholar
  97. Hernandez RV et al (2016) Transgenic mice with increased astrocyte expression of IL-6 show altered effects of acute ethanol on synaptic function. Neuropharmacology 103:27–43PubMedGoogle Scholar
  98. Herrmann O et al (2003) Regulation of body temperature and neuroprotection by endogenous interleukin-6 in cerebral ischemia. J Cereb Blood Flow Metab 23(4):406–415PubMedGoogle Scholar
  99. Holmes A, Wellman CL (2009) Stress-induced prefrontal reorganization and executive dysfunction in rodents. Neurosci Biobehav Rev 33(6):773–783PubMedGoogle Scholar
  100. Hosoi T, Okuma Y, Nomura Y (2002a) The mechanisms of immune-to-brain communication in inflammation as a drug target. Curr Drug Targets Inflamm Allergy 1(3):257–262PubMedGoogle Scholar
  101. Hosoi T, Okuma Y, Nomura Y (2002b) Leptin induces IL-1 receptor antagonist expression in the brain. Biochem Biophys Res Commun 294(2):215–219PubMedGoogle Scholar
  102. Hyytia P, Koob GF (1995) GABAA receptor antagonism in the extended amygdala decreases ethanol self-administration in rats. Eur J Pharmacol 283(1–3):151–159PubMedGoogle Scholar
  103. Johnson JD et al (2004) The role of IL-1beta in stress-induced sensitization of proinflammatory cytokine and corticosterone responses. Neuroscience 127(3):569–577PubMedGoogle Scholar
  104. June HL et al (2015) CRF-amplified neuronal TLR4/MCP-1 signaling regulates alcohol self-administration. Neuropsychopharmacology 40(6):1549–1559PubMedPubMedCentralGoogle Scholar
  105. Jung H et al (2008) Monocyte chemoattractant protein-1 functions as a neuromodulator in dorsal root ganglia neurons. J Neurochem 104(1):254–263PubMedGoogle Scholar
  106. Kamdar NK et al (2007) Acute effects of naltrexone and GBR 12909 on ethanol drinking-in-the-dark in C57BL/6J mice. Psychopharmacology 192(2):207–217PubMedGoogle Scholar
  107. Kane CJ et al (2013) Effects of ethanol on immune response in the brain: region-specific changes in aged mice. J Neuroinflammation 10:66PubMedPubMedCentralGoogle Scholar
  108. Kane CJ et al (2014) Effects of ethanol on immune response in the brain: region-specific changes in adolescent versus adult mice. Alcohol Clin Exp Res 38(2):384–391PubMedGoogle Scholar
  109. Kaneko M et al (2008) Tumor necrosis factor-alpha mediates one component of competitive, experience-dependent plasticity in developing visual cortex. Neuron 58(5):673–680PubMedPubMedCentralGoogle Scholar
  110. Keyel PA (2014) How is inflammation initiated? Individual influences of IL-1, IL-18 and HMGB1. Cytokine 69(1):136–145PubMedGoogle Scholar
  111. Kiefer F et al (2002) Alcohol intake, tumour necrosis factor-alpha, leptin and craving: factors of a possibly vicious circle? Alcohol Alcohol 37(4):401–404PubMedGoogle Scholar
  112. Klausberger T, Somogyi P (2008) Neuronal diversity and temporal dynamics: the unity of hippocampal circuit operations. Science 321(5885):53–57PubMedPubMedCentralGoogle Scholar
  113. Knapp DJ et al (2011) Cytokine involvement in stress may depend on corticotrophin releasing factor to sensitize ethanol withdrawal anxiety. Brain Behav Immun 25(Suppl 1):S146–S154PubMedPubMedCentralGoogle Scholar
  114. Knapp DJ et al (2016) Stress and withdrawal from chronic ethanol induce selective changes in neuroimmune mRNAs in differing brain sites. Brain Sci 6(3).
  115. Kohman RA, Rhodes JS (2013) Neurogenesis, inflammation and behavior. Brain Behav Immun 27(1):22–32PubMedGoogle Scholar
  116. Konsman JP et al (2008) Central nervous action of interleukin-1 mediates activation of limbic structures and behavioural depression in response to peripheral administration of bacterial lipopolysaccharide. Eur J Neurosci 28(12):2499–2510PubMedGoogle Scholar
  117. Koo JW, Duman RS (2008) IL-1beta is an essential mediator of the antineurogenic and anhedonic effects of stress. Proc Natl Acad Sci U S A 105(2):751–756PubMedPubMedCentralGoogle Scholar
  118. Koob GF, Volkow ND (2016) Neurobiology of addiction: a neurocircuitry analysis. Lancet Psychiatry 3(8):760–773PubMedPubMedCentralGoogle Scholar
  119. Kreisel T et al (2014) Dynamic microglial alterations underlie stress-induced depressive-like behavior and suppressed neurogenesis. Mol Psychiatry 19:699–709PubMedGoogle Scholar
  120. Kriegler M et al (1988) A novel form of TNF/cachectin is a cell surface cytotoxic transmembrane protein: ramifications for the complex physiology of TNF. Cell 53(1):45–53PubMedGoogle Scholar
  121. Krumm B, Xiang Y, Deng J (2014) Structural biology of the IL-1 superfamily: key cytokines in the regulation of immune and inflammatory responses. Protein Sci 23(5):526–538PubMedPubMedCentralGoogle Scholar
  122. Kuang Y et al (1996) Selective G protein coupling by C-C chemokine receptors. J Biol Chem 271(8):3975–3978PubMedGoogle Scholar
  123. Kwilasz AJ et al (2015) The therapeutic potential of interleukin-10 in neuroimmune diseases. Neuropharmacology 96:55–69PubMedGoogle Scholar
  124. Lamkanfi M, Dixit VM (2014) Mechanisms and functions of inflammasomes. Cell 157(5):1013–1022PubMedGoogle Scholar
  125. Lawrimore CJ, Crews FT (2017) Ethanol, TLR3, and TLR4 agonists have unique innate immune responses in neuron-like SH-SY5Y and microglia-like BV2. Alcohol Clin Exp Res 41(5):939–954PubMedPubMedCentralGoogle Scholar
  126. Leonoudakis D et al (2004) TNFalpha-induced AMPA-receptor trafficking in CNS neurons; relevance to excitotoxicity? Neuron Glia Biol 1(3):263–273PubMedPubMedCentralGoogle Scholar
  127. Levin SG, Godukhin OV (2017) Modulating effect of cytokines on mechanisms of synaptic plasticity in the brain. Biochemistry (Mosc) 82(3):264–274Google Scholar
  128. Lewohl JM et al (2000) Gene expression in human alcoholism: microarray analysis of frontal cortex. Alcohol Clin Exp Res 24(12):1873–1882PubMedGoogle Scholar
  129. Li X et al (2014) Interleukin-6 inhibits voltage-gated sodium channel activity of cultured rat spinal cord neurons. Acta Neuropsychiatr 26(3):170–177PubMedGoogle Scholar
  130. Librizzi L et al (2012) Seizure-induced brain-borne inflammation sustains seizure recurrence and blood-brain barrier damage. Ann Neurol 72(1):82–90PubMedGoogle Scholar
  131. Lieb K et al (2005) Serotonin via 5-HT7 receptors activates p38 mitogen-activated protein kinase and protein kinase C epsilon resulting in interleukin-6 synthesis in human U373 MG astrocytoma cells. J Neurochem 93(3):549–559PubMedGoogle Scholar
  132. Lim SH et al (2013) Neuronal synapse formation induced by microglia and interleukin 10. PLoS One 8(11):e81218PubMedPubMedCentralGoogle Scholar
  133. Lin HW et al (2006) Astrogliosis is delayed in type 1 interleukin-1 receptor-null mice following a penetrating brain injury. J Neuroinflammation 3:15PubMedPubMedCentralGoogle Scholar
  134. Lippai D et al (2013a) Alcohol-induced IL-1beta in the brain is mediated by NLRP3/ASC inflammasome activation that amplifies neuroinflammation. J Leukoc Biol 94(1):171–182PubMedPubMedCentralGoogle Scholar
  135. Lippai D et al (2013b) Chronic alcohol-induced microRNA-155 contributes to neuroinflammation in a TLR4-dependent manner in mice. PLoS One 8(8):e70945PubMedPubMedCentralGoogle Scholar
  136. Lobo-Silva D et al (2016) Balancing the immune response in the brain: IL-10 and its regulation. J Neuroinflammation 13(1):297PubMedPubMedCentralGoogle Scholar
  137. Lukats B, Egyed R, Karadi Z (2005) Single neuron activity changes to interleukin-1beta in the orbitofrontal cortex of the rat. Brain Res 1038(2):243–246PubMedGoogle Scholar
  138. Lydyard PM et al (2011) Immunology. Garland Science, New YorkGoogle Scholar
  139. Maier SF et al (1998) The role of the vagus nerve in cytokine-to-brain communication. Ann N Y Acad Sci 840:289–300PubMedGoogle Scholar
  140. Maimone D et al (1993) Norepinephrine and vasoactive intestinal peptide induce IL-6 secretion by astrocytes: synergism with IL-1 beta and TNF alpha. J Neuroimmunol 47(1):73–81PubMedGoogle Scholar
  141. Manfridi A et al (2003) Interleukin-1beta enhances non-rapid eye movement sleep when microinjected into the dorsal raphe nucleus and inhibits serotonergic neurons in vitro. Eur J Neurosci 18(5):1041–1049PubMedGoogle Scholar
  142. Marcos M et al (2008) Interleukin-10 gene polymorphism is associated with alcoholism but not with alcoholic liver disease. Alcohol Alcohol 43(5):523–528PubMedGoogle Scholar
  143. Marin I, Kipnis J (2013) Learning and memory … and the immune system. Learn Mem 20(10):601–606PubMedPubMedCentralGoogle Scholar
  144. Marshall SA et al (2013) Microglial activation is not equivalent to neuroinflammation in alcohol-induced neurodegeneration: the importance of microglia phenotype. Neurobiol Dis 54:239–251PubMedPubMedCentralGoogle Scholar
  145. Marshall SA, Geil CR, Nixon K (2016a) Prior binge ethanol exposure potentiates the microglial response in a model of alcohol-induced neurodegeneration. Brain Sci 6(2).
  146. Marshall SA et al (2016b) IL-1 receptor signaling in the basolateral amygdala modulates binge-like ethanol consumption in male C57BL/6J mice. Brain Behav Immun 51:258–267PubMedGoogle Scholar
  147. Marshall SA et al (2017) Modulation of binge-like ethanol consumption by IL-10 signaling in the basolateral amygdala. J Neuroimmune Pharmacol 12(2):249–259PubMedGoogle Scholar
  148. Mastorakos G, Chrousos GP, Weber JS (1993) Recombinant interleukin-6 activates the hypothalamic-pituitary-adrenal axis in humans. J Clin Endocrinol Metab 77(6):1690–1694PubMedGoogle Scholar
  149. McClain JA et al (2011) Adolescent binge alcohol exposure induces long-lasting partial activation of microglia. Brain Behav Immun 25(Suppl 1):S120–S128PubMedPubMedCentralGoogle Scholar
  150. Medvedev AE, Sundan A, Espevik T (1994) Involvement of the tumor necrosis factor receptor p75 in mediating cytotoxicity and gene regulating activities. Eur J Immunol 24(11):2842–2849PubMedGoogle Scholar
  151. Miller LG et al (1991) Interleukin-1 augments gamma-aminobutyric acidA receptor function in brain. Mol Pharmacol 39(2):105–108PubMedGoogle Scholar
  152. Ming Z, Criswell HE, Breese GR (2013) Evidence for TNFalpha action on excitatory and inhibitory neurotransmission in the central amygdala: a brain site influenced by stress. Brain Behav Immun 33:102–111PubMedPubMedCentralGoogle Scholar
  153. Mishra A et al (2012) Synapse loss induced by interleukin-1beta requires pre- and post-synaptic mechanisms. J Neuroimmune Pharmacol 7(3):571–578PubMedPubMedCentralGoogle Scholar
  154. Montesinos J, Alfonso-Loeches S, Guerri C (2016) Impact of the innate immune response in the actions of ethanol on the central nervous system. Alcohol Clin Exp Res 40(11):2260–2270PubMedGoogle Scholar
  155. Montesinos J, Gil A, Guerri C (2017) Nalmefene prevents alcohol-induced neuroinflammation and alcohol drinking preference in adolescent female mice: role of TLR4. Alcohol Clin Exp Res 41(7):1257–1270PubMedGoogle Scholar
  156. Morrow JD, Opp MR (2005) Sleep-wake behavior and responses of interleukin-6-deficient mice to sleep deprivation. Brain Behav Immun 19(1):28–39PubMedGoogle Scholar
  157. Motoki K et al (2009) The direct excitatory effect of IL-1beta on cerebellar Purkinje cell. Biochem Biophys Res Commun 379(3):665–668PubMedGoogle Scholar
  158. Mulligan MK et al (2006) Toward understanding the genetics of alcohol drinking through transcriptome meta-analysis. Proc Natl Acad Sci U S A 103(16):6368–6373PubMedPubMedCentralGoogle Scholar
  159. Murray CA et al (1997) Interleukin-1 beta inhibits glutamate release in hippocampus of young, but not aged, rats. Neurobiol Aging 18(3):343–348PubMedGoogle Scholar
  160. Musumeci G et al (2011) Transient receptor potential vanilloid 1 channels modulate the synaptic effects of TNF-alpha and of IL-1beta in experimental autoimmune encephalomyelitis. Neurobiol Dis 43(3):669–677PubMedGoogle Scholar
  161. Nallar SC, Kalvakolanu DV (2014) Interferons, signal transduction pathways, and the central nervous system. J Interf Cytokine Res 34(8):559–576Google Scholar
  162. Nie Z et al (2004) Ethanol augments GABAergic transmission in the central amygdala via CRF1 receptors. Science 303(5663):1512–1514PubMedGoogle Scholar
  163. Nie Z et al (2009) Presynaptic CRF1 receptors mediate the ethanol enhancement of GABAergic transmission in the mouse central amygdala. Sci World J 9:68–85Google Scholar
  164. Norkina O et al (2007) Acute alcohol activates STAT3, AP-1, and Sp-1 transcription factors via the family of Src kinases to promote IL-10 production in human monocytes. J Leukoc Biol 82(3):752–762PubMedGoogle Scholar
  165. Norris JG, Benveniste EN (1993) Interleukin-6 production by astrocytes: induction by the neurotransmitter norepinephrine. J Neuroimmunol 45(1–2):137–145PubMedGoogle Scholar
  166. Nuss P (2015) Anxiety disorders and GABA neurotransmission: a disturbance of modulation. Neuropsychiatr Dis Treat 11:165–175PubMedPubMedCentralGoogle Scholar
  167. O’Connor JJ, Coogan AN (1999) Actions of the pro-inflammatory cytokine IL-1 beta on central synaptic transmission. Exp Physiol 84(4):601–614PubMedGoogle Scholar
  168. O’Neill LA (2008) The interleukin-1 receptor/toll-like receptor superfamily: 10 years of progress. Immunol Rev 226:10–18PubMedGoogle Scholar
  169. Old EA, Malcangio M (2012) Chemokine mediated neuron-glia communication and aberrant signalling in neuropathic pain states. Curr Opin Pharmacol 12(1):67–73PubMedGoogle Scholar
  170. Orellana DI et al (2005) Role of the JAKs/STATs pathway in the intracellular calcium changes induced by interleukin-6 in hippocampal neurons. Neurotox Res 8(3–4):295–304PubMedGoogle Scholar
  171. Pan W, Kastin AJ (2001) Upregulation of the transport system for TNFalpha at the blood-brain barrier. Arch Physiol Biochem 109(4):350–353PubMedGoogle Scholar
  172. Parker LC et al (2000) IL-1beta induced changes in hypothalamic IL-1R1 and IL-1R2 mRNA expression in the rat. Brain Res Mol Brain Res 79(1–2):156–158PubMedGoogle Scholar
  173. Pascual M et al (2015) Cytokines and chemokines as biomarkers of ethanol-induced neuroinflammation and anxiety-related behavior: role of TLR4 and TLR2. Neuropharmacology 89:352–359PubMedGoogle Scholar
  174. Pascual M et al (2017) Gender differences in the inflammatory cytokine and chemokine profiles induced by binge ethanol drinking in adolescence. Addict Biol 22(6):1829–1841PubMedGoogle Scholar
  175. Pastor IJ et al (2005) Interleukin-1 gene cluster polymorphisms and alcoholism in Spanish men. Alcohol Alcohol 40(3):181–186PubMedGoogle Scholar
  176. Ponomarev I et al (2012) Gene coexpression networks in human brain identify epigenetic modifications in alcohol dependence. J Neurosci 32(5):1884–1897PubMedPubMedCentralGoogle Scholar
  177. Pribiag H, Stellwagen D (2014) Neuroimmune regulation of homeostatic synaptic plasticity. Neuropharmacology 78:13–22PubMedGoogle Scholar
  178. Probert L (2015) TNF and its receptors in the CNS: the essential, the desirable and the deleterious effects. Neuroscience 302:2–22PubMedGoogle Scholar
  179. Qin L, Crews FT (2014) Focal thalamic degeneration from ethanol and thiamine deficiency is associated with neuroimmune gene induction, microglial activation, and lack of monocarboxylic acid transporters. Alcohol Clin Exp Res 38(3):657–671PubMedGoogle Scholar
  180. Qin L et al (2008) Increased systemic and brain cytokine production and neuroinflammation by endotoxin following ethanol treatment. J Neuroinflammation 5:10PubMedPubMedCentralGoogle Scholar
  181. Qiu Z, Parsons KL, Gruol DL (1995) Interleukin-6 selectively enhances the intracellular calcium response to NMDA in developing CNS neurons. J Neurosci 15(10):6688–6699PubMedGoogle Scholar
  182. Quan N et al (1996) Detection of interleukin-1 bioactivity in various brain regions of normal healthy rats. Neuroimmunomodulation 3(1):47–55PubMedGoogle Scholar
  183. Quan N, Whiteside M, Herkenham M (1998) Time course and localization patterns of interleukin-1beta messenger RNA expression in brain and pituitary after peripheral administration of lipopolysaccharide. Neuroscience 83(1):281–293PubMedGoogle Scholar
  184. Rajayer SR et al (2013) Cold-inducible RNA-binding protein is an important mediator of alcohol-induced brain inflammation. PLoS One 8(11):e79430PubMedPubMedCentralGoogle Scholar
  185. Rao P, Hsu KC, Chao MV (1995) Upregulation of NF-kappa B-dependent gene expression mediated by the p75 tumor necrosis factor receptor. J Interf Cytokine Res 15(2):171–177Google Scholar
  186. Reaux-Le Goazigo A et al (2013) Current status of chemokines in the adult CNS. Prog Neurobiol 104:67–92PubMedGoogle Scholar
  187. Roberson R et al (2011) Neuroprotective fractalkine in fetal alcohol syndrome. Am J Obstet Gynecol 204(5):400.e1–3PubMedGoogle Scholar
  188. Roberto M et al (2003) Ethanol increases GABAergic transmission at both pre- and postsynaptic sites in rat central amygdala neurons. Proc Natl Acad Sci U S A 100(4):2053–2058PubMedPubMedCentralGoogle Scholar
  189. Roberto M et al (2010) Corticotropin releasing factor-induced amygdala gamma-aminobutyric Acid release plays a key role in alcohol dependence. Biol Psychiatry 67(9):831–839PubMedPubMedCentralGoogle Scholar
  190. Roberto M, Gilpin NW, Siggins GR (2012) The central amygdala and alcohol: role of gamma-Aminobutyric acid, glutamate, and neuropeptides. Cold Spring Harb Perspect Med 2(12):a012195PubMedPubMedCentralGoogle Scholar
  191. Roberts AJ, Cole M, Koob GF (1996) Intra-amygdala muscimol decreases operant ethanol self-administration in dependent rats. Alcohol Clin Exp Res 20(7):1289–1298PubMedGoogle Scholar
  192. Robinson G et al (2014) Neuroimmune pathways in alcohol consumption: evidence from behavioral and genetic studies in rodents and humans. Int Rev Neurobiol 118:13–39PubMedPubMedCentralGoogle Scholar
  193. Rochfort KD, Cummins PM (2015) The blood-brain barrier endothelium: a target for pro-inflammatory cytokines. Biochem Soc Trans 43(4):702–706PubMedGoogle Scholar
  194. Rostene W, Kitabgi P, Parsadaniantz SM (2007) Chemokines: a new class of neuromodulator? Nat Rev Neurosci 8(11):895–903PubMedGoogle Scholar
  195. Rothwell NJ, Luheshi GN (2000) Interleukin 1 in the brain: biology, pathology and therapeutic target. Trends Neurosci 23(12):618–625PubMedGoogle Scholar
  196. Ryan SM, Nolan YM (2016) Neuroinflammation negatively affects adult hippocampal neurogenesis and cognition: can exercise compensate? Neurosci Biobehav Rev 61:121–131PubMedGoogle Scholar
  197. Sama MA et al (2008) Interleukin-1beta-dependent signaling between astrocytes and neurons depends critically on astrocytic calcineurin/NFAT activity. J Biol Chem 283(32):21953–21964PubMedPubMedCentralGoogle Scholar
  198. Sarc L, Wraber B, Lipnik-Stangelj M (2011) Ethanol and acetaldehyde disturb TNF-alpha and IL-6 production in cultured astrocytes. Hum Exp Toxicol 30(9):1256–1265PubMedGoogle Scholar
  199. Schaper F, Rose-John S (2015) Interleukin-6: biology, signaling and strategies of blockade. Cytokine Growth Factor Rev 26(5):475–487PubMedGoogle Scholar
  200. Schneider R Jr et al (2017) N-acetylcysteine prevents alcohol related neuroinflammation in rats. Neurochem Res 42(8):2135–2141PubMedGoogle Scholar
  201. Schunck RV et al (2015) Protracted alcohol abstinence induces analgesia in rats: possible relationships with BDNF and interleukin-10. Pharmacol Biochem Behav 135:64–69PubMedGoogle Scholar
  202. Sedger LM, McDermott MF (2014) TNF and TNF-receptors: from mediators of cell death and inflammation to therapeutic giants – past, present and future. Cytokine Growth Factor Rev 25(4):453–472PubMedGoogle Scholar
  203. Segev-Amzaleg N, Trudler D, Frenkel D (2013) Preconditioning to mild oxidative stress mediates astroglial neuroprotection in an IL-10-dependent manner. Brain Behav Immun 30:176–185PubMedGoogle Scholar
  204. Semple BD, Frugier T, Morganti-Kossmann MC (2010) CCL2 modulates cytokine production in cultured mouse astrocytes. J Neuroinflammation 7:67PubMedPubMedCentralGoogle Scholar
  205. Serantes R et al (2006) Interleukin-1beta enhances GABAA receptor cell-surface expression by a phosphatidylinositol 3-kinase/Akt pathway: relevance to sepsis-associated encephalopathy. J Biol Chem 281(21):14632–14643PubMedGoogle Scholar
  206. Sery O et al (2003) Association between -174 G/C polymorphism of interleukin-6 gene and alcoholism. Acta Neuropsychiatr 15(5):257–261PubMedGoogle Scholar
  207. Sharma S et al (2011) IL-10 directly protects cortical neurons by activating PI-3 kinase and STAT-3 pathways. Brain Res 1373:189–194PubMedGoogle Scholar
  208. Silveri MM (2014) GABAergic contributions to alcohol responsivity during adolescence: insights from preclinical and clinical studies. Pharmacol Ther 143(2):197–216PubMedPubMedCentralGoogle Scholar
  209. Stellwagen D, Malenka RC (2006) Synaptic scaling mediated by glial TNF-alpha. Nature 440(7087):1054–1059PubMedGoogle Scholar
  210. Stellwagen D et al (2005) Differential regulation of AMPA receptor and GABA receptor trafficking by tumor necrosis factor-alpha. J Neurosci 25(12):3219–3228PubMedGoogle Scholar
  211. Stopponi S et al (2011) Activation of nuclear PPARgamma receptors by the antidiabetic agent pioglitazone suppresses alcohol drinking and relapse to alcohol seeking. Biol Psychiatry 69(7):642–649PubMedGoogle Scholar
  212. Stopponi S et al (2013) Activation of PPARgamma by pioglitazone potentiates the effects of naltrexone on alcohol drinking and relapse in msP rats. Alcohol Clin Exp Res 37(8):1351–1360PubMedGoogle Scholar
  213. Suryanarayanan A et al (2016) Role of interleukin-10 (IL-10) in regulation of GABAergic transmission and acute response to ethanol. Neuropharmacology 107:181–188PubMedPubMedCentralGoogle Scholar
  214. Szabo G, Lippai D (2014) Converging actions of alcohol on liver and brain immune signaling. Int Rev Neurobiol 118:359–380PubMedGoogle Scholar
  215. Szabo G, Saha B (2015) Alcohol’s effect on host defense. Alcohol Res 37(2):159–170PubMedPubMedCentralGoogle Scholar
  216. Tabarean IV, Korn H, Bartfai T (2006) Interleukin-1beta induces hyperpolarization and modulates synaptic inhibition in preoptic and anterior hypothalamic neurons. Neuroscience 141(4):1685–1695PubMedGoogle Scholar
  217. Taishi P et al (1997) Diurnal variations of interleukin-1 beta mRNA and beta-actin mRNA in rat brain. J Neuroimmunol 75(1–2):69–74PubMedGoogle Scholar
  218. Takao T et al (1990) Interleukin-1 receptors in mouse brain: characterization and neuronal localization. Endocrinology 127(6):3070–3078PubMedGoogle Scholar
  219. Takeuchi H et al (2006) Tumor necrosis factor-alpha induces neurotoxicity via glutamate release from hemichannels of activated microglia in an autocrine manner. J Biol Chem 281(30):21362–21368PubMedGoogle Scholar
  220. Teng SX, Molina PE (2014) Acute alcohol intoxication prolongs neuroinflammation without exacerbating neurobehavioral dysfunction following mild traumatic brain injury. J Neurotrauma 31(4):378–386PubMedPubMedCentralGoogle Scholar
  221. Tiwari V, Chopra K (2012) Attenuation of oxidative stress, neuroinflammation, and apoptosis by curcumin prevents cognitive deficits in rats postnatally exposed to ethanol. Psychopharmacology 224(4):519–535PubMedGoogle Scholar
  222. Tiwari V, Chopra K (2013) Resveratrol abrogates alcohol-induced cognitive deficits by attenuating oxidative-nitrosative stress and inflammatory cascade in the adult rat brain. Neurochem Int 62(6):861–869PubMedGoogle Scholar
  223. Tomie A, Azogu I, Yu L (2013) Effects of naltrexone on post-abstinence alcohol drinking in C57BL/6NCRL and DBA/2J mice. Prog Neuro-Psychopharmacol Biol Psychiatry 44:240–247Google Scholar
  224. Topper LA, Baculis BC, Valenzuela CF (2015) Exposure of neonatal rats to alcohol has differential effects on neuroinflammation and neuronal survival in the cerebellum and hippocampus. J Neuroinflammation 12:160PubMedPubMedCentralGoogle Scholar
  225. Towne JE et al (2004) Interleukin (IL)-1F6, IL-1F8, and IL-1F9 signal through IL-1Rrp2 and IL-1RAcP to activate the pathway leading to NF-kappaB and MAPKs. J Biol Chem 279(14):13677–13688PubMedGoogle Scholar
  226. Tsao N et al (2001) Tumour necrosis factor-alpha causes an increase in blood-brain barrier permeability during sepsis. J Med Microbiol 50(9):812–821PubMedGoogle Scholar
  227. Turrigiano GG (2008) The self-tuning neuron: synaptic scaling of excitatory synapses. Cell 135(3):422–435PubMedPubMedCentralGoogle Scholar
  228. Umhau JC et al (2014) Cerebrospinal fluid monocyte chemoattractant protein-1 in alcoholics: support for a neuroinflammatory model of chronic alcoholism. Alcohol Clin Exp Res 38(5):1301–1306PubMedGoogle Scholar
  229. Uryu K et al (1992) Fine structure and possible origins of nerve fibers with corticotropin-releasing factor-like immunoreactivity in the rat central amygdaloid nucleus. Brain Res 577(1):175–179PubMedGoogle Scholar
  230. Valenta JP, Gonzales RA (2016) Chronic intracerebroventricular infusion of monocyte chemoattractant Protein-1 leads to a persistent increase in sweetened ethanol consumption during operant self-administration but does not influence sucrose consumption in long-evans rats. Alcohol Clin Exp Res 40(1):187–195PubMedGoogle Scholar
  231. Valles SL et al (2004) Chronic ethanol treatment enhances inflammatory mediators and cell death in the brain and in astrocytes. Brain Pathol 14(4):365–371PubMedGoogle Scholar
  232. Vetreno RP, Qin L, Crews FT (2013) Increased receptor for advanced glycation end product expression in the human alcoholic prefrontal cortex is linked to adolescent drinking. Neurobiol Dis 59:52–62PubMedPubMedCentralGoogle Scholar
  233. Vezzani A, Friedman A (2011) Brain inflammation as a biomarker in epilepsy. Biomark Med 5(5):607–614PubMedPubMedCentralGoogle Scholar
  234. Vezzani A, Viviani B (2015) Neuromodulatory properties of inflammatory cytokines and their impact on neuronal excitability. Neuropharmacology 96(Pt A):70–82PubMedGoogle Scholar
  235. Vezzani A et al (1999) Interleukin-1beta immunoreactivity and microglia are enhanced in the rat hippocampus by focal kainate application: functional evidence for enhancement of electrographic seizures. J Neurosci 19(12):5054–5065PubMedGoogle Scholar
  236. Vezzani A et al (2011) The role of inflammation in epilepsy. Nat Rev Neurol 7(1):31–40PubMedGoogle Scholar
  237. Viviani B et al (2003) Interleukin-1beta enhances NMDA receptor-mediated intracellular calcium increase through activation of the Src family of kinases. J Neurosci 23(25):8692–8700PubMedGoogle Scholar
  238. Viviani B et al (2014) Early maternal deprivation immunologically primes hippocampal synapses by redistributing interleukin-1 receptor type I in a sex dependent manner. Brain Behav Immun 35:135–143PubMedGoogle Scholar
  239. Vosshenrich CA, Di Santo JP (2002) Interleukin signaling. Curr Biol 12(22):R760–R763PubMedGoogle Scholar
  240. Wain JH, Kirby JA, Ali S (2002) Leucocyte chemotaxis: examination of mitogen-activated protein kinase and phosphoinositide 3-kinase activation by Monocyte Chemoattractant Proteins-1, -2, -3 and -4. Clin Exp Immunol 127(3):436–444PubMedPubMedCentralGoogle Scholar
  241. Walczak H (2011) TNF and ubiquitin at the crossroads of gene activation, cell death, inflammation, and cancer. Immunol Rev 244(1):9–28PubMedGoogle Scholar
  242. Wallenius V et al (2002) Interleukin-6-deficient mice develop mature-onset obesity. Nat Med 8(1):75–79PubMedGoogle Scholar
  243. Wang DS et al (2012) Memory deficits induced by inflammation are regulated by alpha5-subunit-containing GABAA receptors. Cell Rep 2(3):488–496PubMedPubMedCentralGoogle Scholar
  244. Wang X et al (2015) Ethanol directly induced HMGB1 release through NOX2/NLRP1 inflammasome in neuronal cells. Toxicology 334:104–110PubMedGoogle Scholar
  245. Whitman BA et al (2013) The cytokine mRNA increase induced by withdrawal from chronic ethanol in the sterile environment of brain is mediated by CRF and HMGB1 release. Alcohol Clin Exp Res 37:2086–2097PubMedGoogle Scholar
  246. Wilhelm CJ et al (2016) Astrocyte dysfunction induced by alcohol in females but not males. Brain Pathol 26(4):433–451PubMedGoogle Scholar
  247. Williamson LL, Bilbo SD (2013) Chemokines and the hippocampus: a new perspective on hippocampal plasticity and vulnerability. Brain Behav Immun 30:186–194PubMedGoogle Scholar
  248. Wu Y et al (2011) Attenuation of microglial and IL-1 signaling protects mice from acute alcohol-induced sedation and/or motor impairment. Brain Behav Immun 25(Suppl 1):S155–S164PubMedGoogle Scholar
  249. Wu Y et al (2012) Inhibiting the TLR4-MyD88 signalling cascade by genetic or pharmacological strategies reduces acute alcohol-induced sedation and motor impairment in mice. Br J Pharmacol 165(5):1319–1329PubMedPubMedCentralGoogle Scholar
  250. Yamasaki T et al (2012) Tumor microvasculature with endothelial fenestrations in VHL null clear cell renal cell carcinomas as a potent target of anti-angiogenic therapy. Cancer Sci 103(11):2027–2037PubMedGoogle Scholar
  251. Ye SM, Johnson RW (1999) Increased interleukin-6 expression by microglia from brain of aged mice. J Neuroimmunol 93(1–2):139–148PubMedGoogle Scholar
  252. Yu B, Shinnick-Gallagher P (1994) Interleukin-1 beta inhibits synaptic transmission and induces membrane hyperpolarization in amygdala neurons. J Pharmacol Exp Ther 271(2):590–600PubMedGoogle Scholar
  253. Zahr NM et al (2010) Measurement of serum, liver, and brain cytokine induction, thiamine levels, and hepatopathology in rats exposed to a 4-day alcohol binge protocol. Alcohol Clin Exp Res 34(11):1858–1870PubMedPubMedCentralGoogle Scholar
  254. Zeise ML, Madamba S, Siggins GR (1992) Interleukin-1 beta increases synaptic inhibition in rat hippocampal pyramidal neurons in vitro. Regul Pept 39(1):1–7PubMedGoogle Scholar
  255. Zeise ML et al (1997) Interleukin-1beta does not increase synaptic inhibition in hippocampal CA3 pyramidal and dentate gyrus granule cells of the rat in vitro. Brain Res 768(1–2):341–344PubMedGoogle Scholar
  256. Zhao P et al (2010) Cannabinoid receptor activation reduces TNFalpha-induced surface localization of AMPAR-type glutamate receptors and excitotoxicity. Neuropharmacology 58(2):551–558PubMedGoogle Scholar
  257. Zhou Y et al (2011) Chemokine CCL2 modulation of neuronal excitability and synaptic transmission in rat hippocampal slices. J Neurochem 116(3):406–414PubMedGoogle Scholar
  258. Zhu G et al (2006) Effects of interleukin-1beta on hippocampal glutamate and GABA releases associated with Ca2+-induced Ca2+ releasing systems. Epilepsy Res 71:107–116Google Scholar
  259. Zhu Q et al (2007) Vitamin E prevents ethanol-induced inflammatory, hormonal, and cytotoxic changes in reproductive tissues. Endocrine 32(1):59–68PubMedGoogle Scholar
  260. Zou JY, Crews FT (2005) TNF alpha potentiates glutamate neurotoxicity by inhibiting glutamate uptake in organotypic brain slice cultures: neuroprotection by NF kappa B inhibition. Brain Res 1034(1–2):11–24PubMedGoogle Scholar
  261. Zou J, Crews FT (2012) Inflammasome-IL-1beta signaling mediates ethanol inhibition of hippocampal neurogenesis. Front Neurosci 6:77PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Department of NeuroscienceThe Scripps Research InstituteLa JollaUSA

Personalised recommendations