Suppression of Innate Immunity by Acute Ethanol Administration: A Global Perspective and a New Mechanism Beginning with Inhibition of Signaling through TLR3

Abstract

Excessive consumption of ethanol (EtOH) suppresses innate immunity, but the mechanisms have not been fully delineated. The present study was conducted to determine whether EtOH suppresses TLR signaling in vivo in mice and to characterize the downstream effects of such suppression. Degradation of IL-1R-associated kinase 1 induced by a TLR3 ligand in peritoneal cells (∼90% macrophages) was suppressed by EtOH. Phosphorylation of p38 kinase in peritoneal macrophages (F4/80+) was suppressed, as was nuclear translocation of p-c-Jun and p65 in peritoneal cells. EtOH decreased IL-6 and IL-12 (p40), but did not significantly affect IL-10 in peritoneal lavage fluid or in lysates of peritoneal cells. Changes in cytokine mRNAs (by RNase protection assay) in macrophages isolated by cell sorting or using Ficoll were generally consistent with changes in protein levels in cell lysates and peritoneal lavage fluid. Thus, suppression of TLR signaling and cytokine mRNA occurred in the same cells, and this suppression generally corresponded to changes in i.p. and intracellular cytokine concentrations. DNA microarray analysis revealed the suppression of an IFN-related amplification loop in peritoneal macrophages, associated with decreased expression of numerous innate immune effector genes (including cytokines and a chemokine also suppressed at the protein level). These results indicate that EtOH suppresses innate immunity at least in part by suppressing TLR3 signaling, suppressing an IFN-related amplification loop, and suppressing the induction of a wide range of innate effector molecules in addition to proinflammatory cytokines and chemokines.

Abrogation of the Antifibrotic Effects of Natural Killer Cells/Interferon-γ Contributes to Alcohol Acceleration of Liver Fibrosis

“…38 In addition, Pruett et al 39 recently reported that ethanol inhibited poly I:C activation of Toll-like receptor 3 (TLR3) signaling in macrophages. It is plausible then to speculate that ethanol may also inhibit TLR3 signaling in NK cells, contributing to ethanol inhibition of NK cell activity.…”

Ethanol Inhibits Antigen Presentation by Dendritic Cells

“…Ethanol has been reported to inhibit the functioning of multiple components of the immune system; both innate immune cells, such as neutrophils, monocytes, macrophages, and dendritic cells (DCs), and B and effector T cells involved in adaptive immunity are adversely affected in both in vitro and in vivo ethanol exposure models. Several signaling pathways found in innate immune cells, involving cytokines, Toll-like receptors (TLRs) 2, 3, 4, and 9, and their downstream targets, such as NF-B as well as signal transducers and activators of transcription (STAT), have been reported to be affected negatively by acute and chronic ethanol exposure (11,12,(22)(23)(24)27). In addition, secretion of the proinflammatory cytokines interleukin-1␤ (IL-1␤), tumor necrosis factor alpha (TNF-␣), and IL-6 has been found to be altered as well (1).…”

The toll-like receptor 3 pathway in homeostasis, responses to injury and wound repair

“…This in turn inhibited the progression of inflammation and liver damage [81,82]. Interestingly, in an alcohol-induced liver injury model, TLR3 signalling activated HSC and Kupffer cells to produce the antiinflammatory cytokine IL-10, which subsequently antagonized TLR4 signalling and minimized liver injury [84]. Another study showed that poly(IC) treatment suppressed inflammation and fat accumulation in the liver of alcohol-injured mice [80].…”