title: TLR2- and TLR4-mediated signals determine attenuation or augmentation of inflammation by acute alcohol in monocytes.
abstract: Most pathogens express ligands for multiple TLRs that share common downstream signaling. In this study, we investigated the effects of acute alcohol on inflammatory pathways induced by TLR2 or TLR4 ligands and their combination. In human monocytes, alcohol attenuated TLR4- but not TLR2-induced TNF-alpha protein and mRNA levels and NF-kappaB activation. In contrast, acute alcohol augmented TNF-alpha production when both TLR2 and TLR4 ligands were present. IL-1R-associated kinase (IRAK)-1 activity was reduced by alcohol in TLR4, but it was augmented in TLR2- plus TLR4-stimulated cells. IRAK-monocyte, an inhibitor of IRAK-1, was induced in TLR4, but it was reduced in TLR2- plus TLR4-stimulated monocytes by alcohol. This was supported by decreased IRAK-1:TRAF6 association in TLR4 induced but sustained presence of IRAK-1:TRAF6 complexes in TLR2- plus TLR4-stimulated monocytes after alcohol treatment. Phosphorylation of MAPKs such as ERK1/2 was selectively inhibited by acute alcohol in TLR4-stimulated cells. In contrast, JNK phosphorylation as well as AP-1 nuclear binding were augmented by acute alcohol in the presence of combined TLR4 and TLR2 stimulation. Consistent with this result, the JNK inhibitor prevented alcohol-induced augmentation of TNF-alpha production. These results suggest that acute alcohol attenuates TLR4-induced inflammation via inhibition of IRAK-1 and ERK1/2 kinases and increases in IRAK-monocyte levels in monocytes. Conversely, in the presence of TLR2 and TLR4 ligands, acute alcohol augments inflammatory responses via IRAK-1 activation and JNK phosphorylation. Thus, the complexity of TLR-mediated signals may determine attenuation or augmentation of inflammatory responses by acute alcohol.
authors.affiliation: Liver Center, Division of Gastroenterology, Department of Medicine, University of Massachusetts Medical School, Worcester, 01605, USA.
authors.forename: Shilpa
authors.initials: S
authors.lastname: Oak
authors.forename: Pranoti
authors.initials: P
authors.lastname: Mandrekar
authors.forename: Donna
authors.initials: D
authors.lastname: Catalano
authors.forename: Karen
authors.initials: K
authors.lastname: Kodys
authors.forename: Gyongyi
authors.initials: G
authors.lastname: Szabo
mesh_terms: D000276:Adjuvants, Immunologic / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D000431:Ethanol / Q000633:toxicity*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000201:enzymology / Q000276:immunology; D053592:Interleukin-1 Receptor-Associated Kinases; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism / Q000502:physiology; D008024:Ligands; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000378:metabolism / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D000276:Adjuvants, Immunologic; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; D053592:Interleukin-1 Receptor-Associated Kinases; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases