Chronic Ethanol Feeding Modulates Inflammatory Mediators, Activation of Nuclear Factor-κB, and Responsiveness to Endotoxin in Murine Kupffer Cells and Circulating Leukocytes

Abstract

Chronic ethanol abuse is known to increase susceptibility to infections after injury, in part, by modification of macrophage function. Several intracellular signalling mechanisms are involved in the initiation of inflammatory responses, including the nuclear factor-κB (NF-κB) pathway. In this study, we investigated the systemic and hepatic effect of chronic ethanol feeding onin vivoactivation of NF-κB in NF-κBEGFPreporter gene mice. Specifically, the study focused on Kupffer cell proinflammatory cytokines IL-6 and TNF-αand activation of NF-κB after chronic ethanol feeding followed byin vitrostimulation with lipopolysaccharide (LPS). We found that chronic ethanol upregulated NF-κB activation and increased hepatic and systemic proinflammatory cytokine levels. Similarly, LPS-stimulated IL-1βrelease from whole blood was significantly enhanced in ethanol-fed mice. However, LPS significantly increased IL-6 and TNF-αlevels. These results demonstrate that chronic ethanol feeding can improve the responsiveness of macrophage LPS-stimulated IL-6 and TNF-αproduction and indicate that this effect may result from ethanol-induced alterations in intracellular signalling through NF-κB. Furthermore, LPS and TNF-αstimulated the gene expression of different inflammatory mediators, in part, in a NF-κB-dependent manner.