TLR2- and TLR4-mediated signals determine attenuation or augmentation of inflammation by acute alcohol in monocytes

Shilpa Oak, Pranoti Mandrekar, Donna Catalano, Karen Kodys, Gyongyi Szabo

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63 Citations (Scopus)

Abstract

Most pathogens express ligands for multiple TLRs that share common downstream signalling. 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-α protein and mRNA levels and NF-κB activation. In contrast, acute alcohol augmented TNF-α 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-α 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.

Original languageEnglish
Pages (from-to)7628-7635
Number of pages8
JournalJournal of Immunology
Volume176
Issue number12
DOIs
Publication statusPublished - Jun 15 2006

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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