title: Inhibition of TLR8- and TLR4-induced Type I IFN induction by alcohol is different from its effects on inflammatory cytokine production in monocytes.
abstract: BACKGROUND
  Prolonged alcohol consumption is a significant co-factor in the progression of chronic viral infections including hepatitis C and HIV, which are both single-stranded RNA viruses. Toll like receptor 8 (TLR8), a pattern recognition receptor expressed in monocytes, senses viral single stranded RNA as a danger signal and leads to the induction of Type I interferon (IFN) as well as the pro-inflammatory cytokine, tumor necrosis factor alpha (TNF alpha). Lipopolysaccharide (LPS), a Toll like receptor 4 (TLR4) ligand, was shown to affect inflammatory cell activation after alcohol consumption and in HIV and HCV infections. Here we hypothesized that alcohol exposure modulates TLR8- and TLR4-ligand-induced monocyte activation and affects both type I IFN and inflammatory cytokine induction.
  
  
  RESULTS
  The TLR8 ligand, CL075, as well as the TLR4 ligand, LPS, resulted in a significant induction of TNF alpha both at the mRNA and protein levels in human monocytes. We found that both acute and prolonged alcohol treatment resulted in inhibition of type I IFN induction by either TLR8 or TLR4 ligands in human monocytes at the protein and mRNA levels. In contrast to Type I IFN production, the effects of acute and prolonged alcohol were different on inflammatory cytokine activation after TLR8 or TLR4 ligand stimulation. Acute alcohol inhibited TLR8- or TLR4-induced TNF alpha protein and mRNA induction while it augmented IL-10 production in monocytes. In contrast, prolonged alcohol treatment augmented TNF alpha without affecting IL-10 production significantly in response to either TLR8 or TLR4 ligand stimulation.
  
  
  CONCLUSIONS
  These novel results suggest first, that alcohol has a profound inhibitory effect on Type I IFN induction regardless of intracellular (TLR8) or cell surface-derived (TLR4) danger signals. Second, both acute and prolonged alcohol exposure can inhibit antiviral Type I IFN pathway activation. Third, the opposite effects of acute (inhibitory) and prolonged alcohol (augmentation) treatment on pro-inflammatory cytokine activation extend to TLR8-induced signals beyond the previously shown TLR4/LPS pathway.
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA.
authors.forename: Maoyin
authors.initials: M
authors.lastname: Pang
authors.forename: Shashi
authors.initials: S
authors.lastname: Bala
authors.forename: Karen
authors.initials: K
authors.lastname: Kodys
authors.forename: Donna
authors.initials: D
authors.lastname: Catalano
authors.forename: Gyongyi
authors.initials: G
authors.lastname: Szabo
mesh_terms: D002478:Cells, Cultured; D000431:Ethanol / Q000494:pharmacology*; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism*; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000819:agonists; D051200:Toll-Like Receptor 8 / Q000819:agonists; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: C551788:CL 075; D018836:Inflammation Mediators; D007370:Interferon Type I; D008070:Lipopolysaccharides; D011804:Quinolines; C495345:TLR4 protein, human; C495349:TLR8 protein, human; D013844:Thiazoles; D051197:Toll-Like Receptor 4; D051200:Toll-Like Receptor 8; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol