SUPPRESSION OF TUMOR-NECROSIS-FACTOR PRODUCTION BY ALCOHOL IN LIPOPOLYSACCHARIDE-STIMULATED CULTURE

Many studies have shown that alcohol consumption is associated with al teration in immune responses and increased incidence of infection in t he host. Tumor necrosis factor (TNF) is a potent soluble mediator of i mmunoregulation and inflammation, and plays a very important role in h ost's defenses against infection and tumor. We propose that one of the mechanisms of alcohol-mediated immunosuppression may be due to a defe ct in the synthesis and release of the TNF. To determine this, we stud ied the direct effect of alcohol on lipopolysaccharide (LPS) induced T NF production by whole blood and total mononuclear cell from normal su bjects. Aliquots of blood samples (1 ml) or ficoll-hypaque separated t otal mononuclear cells (1 x 10(8)/ml) were cultured with different con centrations of either ethanol or acetaldehyde in the presence or absen ce of LPS for 4 hr at 37 degrees C. Plasma samples and culture superna tants were assayed for TNF levels in a bioassay using a TNF-sensitive WEHI 164 subclone 13 cell line. LPS at 10 mu g/ml produced a maximal l evel of TNF compared with lower(l mu g/ml) or higher concentration (50 mu g/ml) of LPS. Kinetics studies showed that an incubation time of 4 hr with LPS produced a maximum level of TNF production by blood. Alco hol, as low as 0.1% concentration, produced significant suppression of LPS-inducted TNF production by whole blood, whereas alcohol at 0.2 an d 0.3% concentrations were required to produce a significant suppressi on of TNF production by separated mononuclear cells. Anti-TNF-alpha an tibodies significantly neutralized the LPS-induced TNF that suggests t hat blood monocytes may be the primary source of TNF production. Furth er, significant correlation between TNF production and monocyte number s was observed. Acetaldehyde one of the primary metabolites of alcohol , did not suppress the LPS induced TNF production by whole blood. Thes e studies suggest that alcohol-induced inhibition of TNF may be one of the mechanisms for immunosuppression in alcoholic patients.