Inhibition of TLR8- and TLR4-induced Type I IFN induction by alcohol is different from its effects on inflammatory cytokine production in monocytes

The TLR8 ligand, CL075, as well as the TLR4 ligand, LPS, resulted in a significant induction of TNF alpha both at the mRNA and protein levels in human monocytes. We found that both acute and prolonged alcohol treatment resulted in inhibition of type I IFN induction by either TLR8 or TLR4 ligands in human monocytes at the protein and mRNA levels. In contrast to Type I IFN production, the effects of acute and prolonged alcohol were different on inflammatory cytokine activation after TLR8 or TLR4 ligand stimulation. Acute alcohol inhibited TLR8- or TLR4-induced TNF alpha protein and mRNA induction while it augmented IL-10 production in monocytes. In contrast, prolonged alcohol treatment augmented TNF alpha without affecting IL-10 production significantly in response to either TLR8 or TLR4 ligand stimulation.These novel results suggest first, that alcohol has a profound inhibitory effect on Type I IFN induction regardless of intracellular (TLR8) or cell surface-derived (TLR4) danger signals. Second, both acute and prolonged alcohol exposure can inhibit antiviral Type I IFN pathway activation. Third, the opposite effects of acute (inhibitory) and prolonged alcohol (augmentation) treatment on pro-inflammatory cytokine activation extend to TLR8-induced signals beyond the previously shown TLR4/LPS pathway.The immunoregulatory effects of acute and chronic alcohol use have been linked to negative clinical outcomes including prolonged recovery after trauma or burn injury, elective surgery, liver disease and infections [1-4]. Excessive alcohol consumption was also identified as an independent risk factor in hepatitis C virus (HCV) infection that leads to chronic infection in up to 80% of cases [5,6]. Excessive alcohol use also affects outcomes in HIV infection and predisposes to advanced disease [7,8]. Both HCV and HIV are single-stranded RNA viruses that induce anti-viral innate immune responses via host pathways that recognize the viral "danger signals" [9-11]. Toll-like rece