Effect of Alcohol Consumption on Markers of Inflammation

Overview

Rationale: High-density lipoprotein (HDL), which is consistently increased after moderate alcohol consumption, is an abundant plasma lipoprotein that is generally thought to be anti-inflammatory in both health and infectious disease. HDL binds and neutralizes the bioactivity of potent bacterial remnants such as lipopolysaccharides (LPS) which stimulate the host innate immune responses. Primary objective: To explore whether prolonged moderate alcohol consumption affects in vivo cytokine response after a low dose of LPS in young, normal-weight men.

Cytokine response in a human model of low-grade systemic inflammation Lipopolysaccharide (LPS) or endotoxin is a constituent of the Gram-negative bacterial cell wall. It circulates in the plasma of healthy human subjects at low concentrations (between 1 and 200 pg/mL). Furthermore, the human gut is host to \~100 trillion organisms, which together contribute to an enteric reservoir of \~1 g LPS (4). Upon introduction in the bloodstream endotoxin binds to LPS-binding protein (LBP) and this complex binds to CD14 on monocytes. CD14 does not have an intracellular domain but signals through Toll-like receptor 4, leading eventually to activation of the transcription factor NF-κB and to production of Tumor Necrosis Factor alpha (TNF-α,) and interleukin 6 (IL-6) and a systemic inflammatory response. Endotoxin administration to humans, when given in a low dose, is a well-established model of systemic inflammation (5). The low dose of endotoxin elicits an acute mild systemic inflammation with a significant and reproducible cytokine and leucocyte response without increases in body temperature (2;3). This model thus resembles the levels reported in chronic low-grade inflammatory conditions such as type 2 diabetes and arthrosclerosis. High-density lipoprotein (HDL) is a group of lipoprotein particles which have the highest density in the circulation. HDL has several anti-atherogenic effects, including the ability to transport excess cellular cholesterol to the liver for excretion, to protect low-density lipoprotein (LDL) against oxidation and to inhibit platelet aggregation. Besides its pivotal role in protecting against atherosclerosis, accumulating evidence also suggest that HDL possesses anti-inflammatory effects and plays an important role in modulating the inflammatory response to lipopolysaccharides. Although all lipoprotein classes have been demonstrated to bind LPS, when added to whole human normal blood, it mainly binds to HDL (60%), in addition to LDL (25%) and VLDL (12%) (6). In vitro, LPS bound to lipoprotein was 20- to 1000-fold less active than the unbound form in inducing monocytes and macrophages to release cytokines (7). When transgenic mice with 2-fold elevation of plasma HDL levels were injected with LPS, they had more LPS bound to HDL, lower plasma cytokine levels, and improved survival rates compared with control mice (8). In humans Ex vivo reconstituted HDL abolished the LPS-induced overproduction of cytokines in patients with severe cirrhosis and controls (9) and intravenous infusion of reconstituted HDL protected humans from the toxic effects of LPS (10). It has never been studied whether the alcohol-induced increase in HDL could attenuate the effects of LPS on cytokine response both ex vivo and in vivo. Given the fact that alcohol induces an increase in HDL (1) and that HDL has LPS-neutralizing properties, it is hypothesized that moderate alcohol consumption attenuates the LPS-induced cytokine response of TNF-α and IL-6 in young, normal-weight men. In addition, because HDL causes down regulation of CD14 expression in monocytes (10) and because CD14 modulates the pro-inflammatory response to LPS (11), the effects of HDL on CD14 expression and expression of other genes related to inflammation will be determined in monocytes over time after both in vivo and ex vivo LPS administration. Since HDL also affects endothelial function (12;13) and since eicosanoids are important messengers during systemic inflammatory processes (14) these markers will also be investigated.

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