High alcohol intake has been shown to compromise cell-mediated and humoral immunity by altering the function of various lymphocytes, including the natural killer (NK) cells, which participate in the defense against infection, tumor development and metastasis. How alcohol alters NK cell function is not known. Preliminary studies using male rats as an animal model demonstrate that alcohol consumption can suppress splenic NK cytolytic activity and decrease hypothalamic and plasma B-endorphin levels. Furthermore, opioid peptide B-endorphin stimulates NK cell cytolytic activity in vitro. Since levels of endogenous B-endorphin are reduced following alcohol treatment, a question arises as to whether the abnormality in NK cell activity in alcohol-treated animals is secondary to altered endogenous opioid activity. The goal of this proposal is to examine the role of opioid peptide B-endorphin in ethanol-modulated NK cell function.
Three specific aims are proposed: 1) to further characterize the effects of ethanol on central and peripheral B-EP by determining the effects on B-EP production and secretion in the hypothalamus and pituitary and ethanol's effects on NK cell cytolytic activity by using NK-enriched splenocytes and 51Cr release assays; 2) to identify the mediatory role of B-EP by determining the actions of B-EP and its antagonist naltrexone on ethanol-modulated NK cell activity, and 3) to determine the neurochemical mechanisms by studying the role of corticotropin-releasing hormone and norepinephrine in B-EP-regulated NK cell activity in alcohol-treated rats. These studies have the potential to elucidate important neuroendocrine mechanisms mediating ethanol-induced immune dysfunction and may indicate potential therapeutic uses of the opiate antagonist naltrexone, in controlling alcohol-induced immune dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
1R01AA012642-01
Application #
2901856
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Isaki, Leslie
Project Start
1999-07-10
Project End
2003-03-31
Budget Start
1999-07-10
Budget End
2000-03-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Rutgers University
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
038633251
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
Boyadjieva, Nadka; Advis, Juan P; Sarkar, Dipak K (2006) Role of beta-endorphin, corticotropin-releasing hormone, and autonomic nervous system in mediation of the effect of chronic ethanol on natural killer cell cytolytic activity. Alcohol Clin Exp Res 30:1761-7
Arjona, Alvaro; Sarkar, Dipak K (2006) Evidence supporting a circadian control of natural killer cell function. Brain Behav Immun 20:469-76
Chen, Cui Ping; Boyadjieva, Nadka I; Advis, Juan P et al. (2006) Ethanol suppression of the hypothalamic proopiomelanocortin level and the splenic NK cell cytolytic activity is associated with a reduction in the expression of proinflammatory cytokines but not anti-inflammatory cytokines in neuroendocrine and immune cel Alcohol Clin Exp Res 30:1925-32
Spanagel, Rainer; Rosenwasser, Alan M; Schumann, Gunter et al. (2005) Alcohol consumption and the body's biological clock. Alcohol Clin Exp Res 29:1550-7
Arjona, Alvaro; Sarkar, Dipak K (2005) Circadian oscillations of clock genes, cytolytic factors, and cytokines in rat NK cells. J Immunol 174:7618-24
Dokur, Madhavi; Chen, Cui Ping; Advis, Juan P et al. (2005) Beta-endorphin modulation of interferon-gamma, perforin and granzyme B levels in splenic NK cells: effects of ethanol. J Neuroimmunol 166:29-38
Boyadjieva, Nadka I; Chaturvedi, Kirti; Poplawski, Michael M et al. (2004) Opioid antagonist naltrexone disrupts feedback interaction between mu and delta opioid receptors in splenocytes to prevent alcohol inhibition of NK cell function. J Immunol 173:42-9
Dokur, Madhavi; Boyadjieva, Nadka; Sarkar, Dipak K (2004) Catecholaminergic control of NK cell cytolytic activity regulatory factors in the spleen. J Neuroimmunol 151:148-57
Arjona, Alvaro; Boyadjieva, Nadka; Sarkar, Dipak K (2004) Circadian rhythms of granzyme B, perforin, IFN-gamma, and NK cell cytolytic activity in the spleen: effects of chronic ethanol. J Immunol 172:2811-7
Chen, Cui Ping; Kuhn, Peter; Advis, Juan P et al. (2004) Chronic ethanol consumption impairs the circadian rhythm of pro-opiomelanocortin and period genes mRNA expression in the hypothalamus of the male rat. J Neurochem 88:1547-54

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