title: Mechanisms of neuroimmune gene induction in alcoholism.
abstract: BACKGROUND
  Alcoholism is a primary, chronic relapsing disease of brain reward, motivation, memory, and related circuitry. It is characterized by an individual's continued drinking despite negative consequences related to alcohol use, which is exemplified by alcohol use leading to clinically significant impairment or distress. Chronic alcohol consumption increases the expression of innate immune signaling molecules (ISMs) in the brain that alter cognitive processes and promote alcohol drinking.
  
  
  OBJECTIVE
  Unraveling the mechanisms of alcohol-induced neuroimmune gene induction is complicated by positive loops of multiple cytokines and other signaling molecules that converge on nuclear factor kappa-light-chain-enhancer of activated B cells and activator protein-1 leading to induction of additional neuroimmune signaling molecules that amplify and expand the expression of ISMs.
  
  
  RESULTS
  Studies from our laboratory employing reverse transcription polymerase chain reaction (RT-PCR) to assess mRNA, immunohistochemistry and Western blot analysis to assess protein expression, and others suggest that ethanol increases brain neuroimmune gene and protein expression through two distinct mechanisms involving (1) systemic induction of innate immune molecules that are transported from blood to the brain and (2) the direct release of high-mobility group box 1 (HMGB1) from neurons in the brain. Released HMGB1 signals through multiple receptors, particularly Toll-like receptor (TLR) 4, that potentiate cytokine receptor responses leading to a hyperexcitable state that disrupts neuronal networks and increases excitotoxic neuronal death. Innate immune gene activation in brain is persistent, consistent with the chronic relapsing disease that is alcoholism. Expression of HMGB1, TLRs, and other ISMs is increased several-fold in the human orbital frontal cortex, and expression of these molecules is highly correlated with each other as well as lifetime alcohol consumption and age of drinking onset.
  
  
  CONCLUSIONS
  The persistent and cumulative nature of alcohol on HMGB1 and TLR gene induction support their involvement in alcohol-induced long-term changes in brain function and neurodegeneration.
authors: Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, School of Medicine, CB# 7178, 1021 Thurston-Bowles Building, Chapel Hill, NC, 27599-7178, USA. fulton_Crews@med.unc.edu.
authors: Fulton T
authors: FT
authors: Crews
authors: Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, School of Medicine, CB# 7178, 1021 Thurston-Bowles Building, Chapel Hill, NC, 27599-7178, USA.
authors: Ryan P
authors: RP
authors: Vetreno
mesh_terms: D000437:Alcoholism / Q000235:genetics* / Q000276:immunology*; D024243:HMGB1 Protein / Q000235:genetics / Q000276:immunology; D006801:Humans; D011598:Psychoneuroimmunology; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology
chemical_list: D024243:HMGB1 Protein; C585491:HMGB1 protein, human; D051193:Toll-Like Receptors
keywords: Alcohol use disorder; Amphoterin; Cytokines; Ethanol; Frontal cortex; Gut permeability; HMGB1; Innate immune; Microglia; RAGE; TLR4