The main goals of this research are to investigate the in vivo immunomodulatory effects of a) acute ethanol exposure alone and b)the combined immunosuppressive potential of alcohol uptake and trauma in humans. Immunosuppressive effects of chronic alcohol use have been reported by a number of investigators. Our data and that of others also demonstrate immunoinhibitory potential of acute ethanol exposure resulting in decreased anti-bacterial defense, depressed inflammatory cytokine production, and altered T cell activation. All of these immune abnormalities could be linked to aberrant monocyte functions found after in vitro acute ethanol exposure. We identified aberrant accessory cell function, decreased pro-inflammatory monokine, and increased inhibitory mediator production in acute ethanol exposed monocyte. We also showed that decreased antigen-specific T cell proliferation after acute ethanol exposure is due to impaired monocyte antigen presenting function, and involves aberrant production of monocyte-derived T cell stimulatory mediators.Consequently, we hypothesize that acute ethanol exposure affects the immune system by altering monocyte accessory capacity, cytokine production, and expression of surface antigens/receptors involved in monocyte-T cell interactions. Aberrant monocyte functions after acute ethanol use would then contribute to impaired T and B lymphocyte, and NK cell functions. Monocyte also play a pivotal role in mediation of post- trauma immunosuppression. Acute ethanol exposure has been shown to increase post-trauma immunosuppression in mice. Our human data also indicate that acute ethanol uptake prior to injury can alter monokine production contributing to post-trauma immunosuppression. Therefore, we further hypothesize that acute ethanol exposure can increase post-trauma immunosuppression via affecting monocyte. These hypotheses will be tested by evaluating the effect of acute in vivo uptake on monocyte functions in normals and in three trauma patient groups: non-alcoholic, alcohol uptake prior to trauma without chronic use, and chronic alcoholic patients. The effects of ethanol alone or with trauma on monocyte-induced aberrant T cell activation will be evaluated in three systems: tetanus toxoid antigen proliferation, superantigen- and mitogen-induced T cell proliferation, each requiring different degrees of monocyte participation. The immunosuppressive role of monocyte derived pro-inflammatory cytokines(TNFalpha, IL-1, IL-6) and inhibitory mediators(TGFbeta ,PGE2, IL-10) will be evaluated by correlating the levels of these cytokines to abnormal monocyte accessory function after acute ethanol exposure alone or with trauma. We will test ethanol-induced mechanisms modulating monocyte susceptibility to subsequent stimulation(bacterial or trauma) by correlating cytokine protein and mRNA levels. Ethanol plus trauma-induced aberrations in monocyte surface antigens/receptor expression(HLA- DR,B7,IFNgammaR), leading to altered monocyte-T cell interactions or monocyte autoregulation, will be identified. We will also test if ethanol alone or with trauma results in a preferential induction or altered function of monocyte subpopulations identified on the basis of surface Fc- gammaRI, CD4, CD33+CD14(dim) expression. Finally, the effects of ethanol plus trauma-induced aberrant monocyte mediator environment affects will be assayed on monocyte differentiation. These experiments will define monocyte alterations leading to the combined immunosuppressive effects of in vivo ethanol uptake and trauma.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA008577-12
Application #
6509178
Study Section
Special Emphasis Panel (ZRG1-ALTX-4 (01))
Program Officer
Lucas, Diane
Project Start
1990-06-01
Project End
2004-03-31
Budget Start
2002-04-01
Budget End
2003-03-31
Support Year
12
Fiscal Year
2002
Total Cost
$404,363
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
660735098
City
Worcester
State
MA
Country
United States
Zip Code
01655
Pang, Maoyin; Bala, Shashi; Kodys, Karen et al. (2011) Inhibition of TLR8- and TLR4-induced Type I IFN induction by alcohol is different from its effects on inflammatory cytokine production in monocytes. BMC Immunol 12:55
Bala, Shashi; Marcos, Miguel; Kodys, Karen et al. (2011) Up-regulation of microRNA-155 in macrophages contributes to increased tumor necrosis factor {alpha} (TNF{alpha}) production via increased mRNA half-life in alcoholic liver disease. J Biol Chem 286:1436-44
Mandrekar, Pranoti; Bala, Shashi; Catalano, Donna et al. (2009) The opposite effects of acute and chronic alcohol on lipopolysaccharide-induced inflammation are linked to IRAK-M in human monocytes. J Immunol 183:1320-7
Dolganiuc, Angela; Petrasek, Jan; Kodys, Karen et al. (2009) MicroRNA expression profile in Lieber-DeCarli diet-induced alcoholic and methionine choline deficient diet-induced nonalcoholic steatohepatitis models in mice. Alcohol Clin Exp Res 33:1704-10
Hoek, Jan; Thiele, Geoffrey M; Klassen, Lynell W et al. (2005) RSA 2004: combined basic research satellite symposium-mechanisms of alcohol-mediated organ and tissue damage: inflammation and immunity and alcohol and mitochondrial metabolism: at the crossroads of life and death session one: alcohol, cellular and organ Alcohol Clin Exp Res 29:1735-43
Szabo, G; Mandrekar, P; Dolganiuc, A et al. (2001) Reduced alloreactive T-cell activation after alcohol intake is due to impaired monocyte accessory cell function and correlates with elevated IL-10, IL-13, and decreased IFNgamma levels. Alcohol Clin Exp Res 25:1766-72
Szabo, G; Gavala, C; Mandrekar, P (2001) Tacrolimus and cyclosporine A inhibit allostimulatory capacity and cytokine production of human myeloid dendritic cells. J Investig Med 49:442-9