Role of beta-endorphin and norepinephrine in alcohol-regulated natural killer cytolytic regulatory factors in the spleen

In the US, alcohol abuse is the third leading cause of death, with treatment costs at nearly {dollar}100 billion annually. Heavy alcohol consumption and binge drinking pose serious health threats including increased risks for cirrhosis, stroke, depression, and cancer. A major complication is immunosuppression. Growing evidence suggests alcohol causes increased tumor metastasis as well as specific defects in natural killer (NK) cell function.; In vivo, alcohol interacts with neuroendocrine mediators of the central and peripheral systems. Alcohol consumption is reinforced by beta-endorphin (beta-EP) and alters central beta-EP level that has immunoregulatory action on NK cells. We hypothesized that altered beta-EP and abnormal activation of the sympathetic nervous system (SNS), and its production of norepinephrine (NE), might provide stimuli for immunosuppression. Involvement of beta-EP and NE in alcohol-regulated NK cell activity and production of perforin, granzyme B and the cytokine interferon (IFN-gamma), regulatory factors critical to NK cell cytoxicity, has not been investigated.; Our results show that the effects of NE and chronic alcohol on NK cell activity and regulatory factors are similar. Exogenous perfusion of beta-EP into the paraventricular nucleus of the hypothalamus increased NK cell cytolytic activity and the mRNA and protein levels of perforin, granzyme B and IFN-gamma in enriched NK cells of pair- and ad lib-fed animals, but not alcohol-fed animals. Alcohol treatment suppressed NK cell activity and decreased mRNA and protein levels of perforin, granzyme B and IFN-gamma. It also prevented beta-EP's stimulatory effect on these cytolytic regulatory factors. Alcohol elevated splenic NE levels; beta-EP lowered them. Furthermore, we showed that in vitro treatment of NE suppressed NK cell cytolytic activity and the mRNA and protein levels of perforin, granzyme B and IFN-gamma. NE's effects were reproduced by beta-adrenergic agonists.; In conclusion, alcohol reduced both basal and beta-EP-induced effects on NK cells. At the central level, it changed beta-EP regulation which can alter SNS activity. At the splenic level, alcohol increased NE content which may inhibit NK cell activation through its inhibitory effect on cytolytic regulatory factors. Understanding the mechanisms of NK cell cytolytic action and inhibition may contribute to treatment of alcohol-related immunological conditions.