Exposure of C57BL/6 mice to 10 daily doses of ethanol followed by LPS results in increased LPS induction of proinflammatory cytokines in the liver, blood, and brain compared with control animals treated only with LPS (Qin et al. 2008). However, this ethanol-induced sensitization to the LPS response resulted in sustained increases in multiple proinflammatory cytokines, including TNF-α, IL-1β, and MCP-1 only in the brain, but not in the liver. The mechanism underlying the sustained brain response and transient liver response is not clear. The investigators noted that the anti-inflammatory cytokine IL-10, which inhibits NF-κB, was increased in the liver 1 week after alcohol treatment, but decreased in the brain (Qin et al. 2008). This suggests that anti-inflammatory mechanisms may contribute to the loss of the liver response. Further analyses found that mice pretreated with ethanol are sensitized not only to the TLR4 receptor agonist LPS but also to the TLR3 agonist Poly:IC (Qin and Crews 2012a). Similar to LPS, Poly:IC induces proinflammatory genes in the brain at 24 hours after 10 days of daily alcohol administration (5 g/kg/day). These findings suggest that chronic ethanol sensitizes proinflammatory TLR responses that are easily observed after the clearance of alcohol.
