Although chronic alcohol treatment increases proinflammatory gene expression in the brain through activation of TLR4, this is confounded by acute alcohol inhibition of TLR4 signaling in monocytes and possibly other cells. Time-dependent acute and chronic opposing effects of ethanol confound many studies (Crews et al. 2006a, 2011; Szabo and Mandrekar 2009). Acute ethanol suppresses the innate immune response to LPS, a TLR4 agonist, in both in vivo and in vitro models. For example, LPS-induced TNF-α and IL-1β production is blunted in blood monocytes obtained from healthy human volunteers after acute alcohol exposure (Crews et al. 2006a; Szabo et al. 1993, 1995, 2001). In animal models, acute ethanol exposure attenuates the TNF-α, IL-1β, and IL-6 immune responses to LPS (Pruett et al. 2004). Similarly, in in vitro models, addition of ethanol (25 mM) just before LPS blunts induction of TNF-α (Szabo et al. 1993, 1995, 2001). In contrast, chronic in vitro ethanol exposure of astrocytes, microglia, and brain slices induces NF-κB transduction of proinflammatory genes through activation of TLR4 signaling (Crews et al. 2013; Fernandez-Lizarbe et al. 2009; Zou and Crews 2014).
