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TLR2- and TLR4-mediated signals determine attenuation or augmentation of inflammation by acute alcohol in monocytes
UMass Chan Affiliations
Department of Medicine, Division of GastroenterologyDepartment of Medicine, Rheumatology Division
Document Type
Journal ArticlePublication Date
2006-06-06Keywords
Adjuvants, ImmunologicAnimals
CHO Cells
Cricetinae
Ethanol
Humans
Inflammation
Interleukin-1 Receptor-Associated Kinases
Intracellular Signaling Peptides and Proteins
Ligands
MAP Kinase Signaling System
Mitogen-Activated Protein Kinases
Monocytes
Protein-Serine-Threonine Kinases
Signal Transduction
Toll-Like Receptor 2
Toll-Like Receptor 4
Tumor Necrosis Factor-alpha
Life Sciences
Medicine and Health Sciences
Metadata
Show full item recordAbstract
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.Source
J Immunol. 2006 Jun 15;176(12):7628-35.
DOI
10.4049/jimmunol.176.12.7628Permanent Link to this Item
http://hdl.handle.net/20.500.14038/38206PubMed ID
16751410Related Resources
ae974a485f413a2113503eed53cd6c53
10.4049/jimmunol.176.12.7628