DOWN-REGULATION OF TUMOR-NECROSIS-FACTOR-ALPHA ACTIVITY BY ACUTE ETHANOL TREATMENT IN HUMAN PERIPHERAL-BLOOD MONOCYTES

As the most commonly used drug that can modulate both metabolic and immune pathways, ethanol is evaluated in this report as a regulator of tumor necrosis factor alpha (TNFalpha) production in human peripheral blood monocytes (Mphi) in combination with a variety of stimuli. While acute ethanol treatment did not induce TNFalpha in Mphi, it was a potent down-regulator of Mphi TNFalpha production whether induced by the combination of interferon-gamma plus muramyl dipeptide (MDP) (P < 0.001), lipopolysaccharide (LPS) alone (P < 0.01), or interferon-gamma plus LPS. Down-regulation of Mphi TNFalpha by ethanol was dose dependent and statistically significant in the biologically relevant, 25-150 mM, ethanol concentration range. We also demonstrate that these ethanol concentrations did not affect Mphi viability. TNFalpha down-regulation by ethanol was most effective when ethanol was administered 4 hr prior to MDP stimulation; however, it was also effective-though to a lesser extent-if it was added at the time of MDP stimulation. Furthermore, ethanol also down-regulated TNFalpha production of the in vivo preactivated Mphi of trauma patients, which produce hyperelevated levels of TNFalpha. We have previously shown that the majority of posttrauma elevated Mphi TNFalpha is produced by the Mphi subpopulation expressing high-affinity type I Fcgamma receptors (FcgammaRI). When the FcgammaRI cross-linking-stimulated Mphi subpopulation was treated with acute ethanol, TNFalpha production was suppressed again both in in vivo preactivated Mphi of trauma patients and in Mphi of normal controls. In experiments utilizing cyclooxygenase inhibitor, we also demonstrate that ethanol has a direct, prostaglandin E2-independent, effect on Mphi TNFalpha production. These results demonstrate that acute ethanol exposure has the potential to down-regulate Mphi production of TNFalpha, significantly regardless of the TNFalpha-inducing stimulus. Decreased capacity of Mphi to produce TNFalpha might, therefore, contribute to the immunological and metabolic abnormalities described after ethanol uptake.