Circulating tumor necrosis factor, interleukin-1 and interleukin-6 concentrations in chronic alcoholic patients

Abstract

Although altered cytokine homeostasis has been implicated in the pathogenesis of alcoholic liver disease, the relationship between cytokines and metabolic consequences of alcoholic liver disease is unknown. We, therefore, sought to correlate circulating concentrations of tumor necrosis factor-alpha, interleukin-1 and interleukin-6 to clinical and biochemical parameters of liver disease in chronic alcoholic patients. We used an enzyme-linked immunosorbent assay to measure plasma tumor necrosis factor and interleukin-1 and a bioassay to measure serum interleukin-6 in three groups of alcoholic men as follows: (a) actively drinking alcoholic men without evidence of chronic liver disease, (b) nondrinking alcoholic men with stable cirrhosis and (c) patients with acute alcoholic hepatitis. Mean cytokine concentrations were elevated in cirrhotic patients and alcoholic hepatitis patients compared with controls and alcoholic patients without liver disease. Tumor necrosis factor-alpha and interleukin-1 alpha concentrations remained elevated for up to 6 mo after diagnosis of alcoholic hepatitis, whereas interleukin-6 normalized in parallel with clinical recovery. Concentrations of all three cytokines were correlated with biochemical parameters of liver injury and hepatic protein synthesis plus serum immunoglobulin concentrations. We could not demonstrate a relationship between cytokine concentrations and peripheral endotoxemia. Percentages of peripheral blood monocytes that reacted with monoclonal antibodies to CD25 (interleukin-2 receptor) and human lymphocyte antigen-DR were similar for alcoholic patients and controls. These data suggest that tumor necrosis factor-alpha and interleukin-1 alpha are related to some of the metabolic consequences of both acute and chronic alcohol-induced liver disease, whereas interleukin-6 is related to abnormalities seen in acute liver injury.

Effect of chronic coadministration of endotoxin and ethanol on rat liver pathology and proinflammatory and anti-inflammatory cytokines

“…18 In patients with various liver diseases, serum concentrations of proinflammatory cytokines TNF-␣, IL-1, and IL-6 are elevated. 19 The hepatic expression of the proinflammatory cytokines TGF-␤ 1 , TNF-␣, and IL-1␤ was recently shown by us to increase preferentially in the perivenous acinar liver region of rats treated chronically with ethanol, 17 which is in line with the early pathological changes seen in this part of the liver acinus.…”

“…Clinically, plasma TNF-␣ concentrations do not reflect improvement in liver disease, although it has some prospective value. 19,45 Most probably, in addition to down-regulation of proinflammatory cytokines, 36 the presumed development of tolerance to endotoxin also involves enhanced endotoxin binding and inactivation by albumin, high density lipoprotein, transferrin, and LBP 56,57 as well as by the reticuloendothelial system. 36,58 Furthermore, the different drinking patterns of the alcoholics may cause temporal variations in their endotoxin levels, which could modify the development of tolerance.…”

Calciphylaxis from Nonuremic Causes

“…Derangements of receptor activator of NF-B (RANK), RANK ligand, and osteoprotegerin may also be involved in the pathogenesis of CUA because this system is involved in regulation of extraskeletal mineralization (42). Some of the factors that predispose to NUC (parathyroid hormone, corticosteroids, and liver disease) are known to increase the expression of RANK ligand and decrease the expression of osteoprotegerin, thus activating NF-B or degrading the inhibitory protein of NF-B (or a combination of these) (43)(44)(45). Warfarin may inhibit vitamin K-dependent carboxylation of matrix-Gla protein, decreasing the activity of the protein to inhibit calcification locally (46).…”

Advances in alcoholic liver disease

“…More than 20 years ago, we first reported that in patients with AH, basal and endotoxin-stimulated monocyte TNF production levels are increased. Subsequent studies showed that plasma and monocyte proinflammatory cytokines correlated with the clinical course of AH and survival [46,47]. Unfortunately, recent human studies have not demonstrated therapeutic efficacy for biologics such as anti-TNF antibody/TNF-soluble receptors in AH [48,49].…”