Journal of Clinical Immunology

, Volume 14, Issue 6, pp 340–352 | Cite as

Acute ethanol consumption synergizes with trauma to increase monocyte tumor necrosis factor α production late postinjury

  • Gyongyi Szabo
  • Pranoti Mandrekar
  • Bikash Verma
  • Ann Isaac
  • Donna Catalano
Original Articles


The hypothesis that acute ethanol uptake plus trauma can synergize to increase immunosuppression was tested. We found that, unlike non-alcohol-exposed patients, patients with acute alcohol use prior to trauma have a transient decrease in monocyte tumor necrosis factor α (TNFα) production during the very early postinjury (0–3 days) period. However, TNFα production by these alcoholexposed patients' monocytes (MØ) became hyperelevated late postinjury (>9 days). Consequently, these massively elevated MØ TNFα levels can contribute to posttrauma immunosuppression after acute alcohol use. We also demonstrate that normal monocyte activation with the superantigen,Staphylococcus enterotoxin B (SEB), results in a preferential induction of cellassociated MØ TNFα production, described as characteristic of immunosuppressed trauma patients. Acutein vitro ethanol treatment down-regulated the elevated TNFα production by trauma patients' MØ after either SEB, muramyl-dipeptide (MDP), interferon-γ plus MDP, or lipopolysaccharide (LPS) stimulation. Both SEB- and LPS-induced TNFα mRNA induction was inhibited by acute alcohol treatment in normal MØ, indicating that ethanol can regulate cytokine gene expression. An additional immunosuppressive effect of acute ethanol's stimulation was suggested by its induction of elevated transforming growth factor β production in trauma patients' activated MØ.

Key words

Immunosuppression superantigens transforming growth factor β prostaglandin E2 cell-associated tumor necrosis factor α 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Deviere J, Content J, Denys C, Vandenbussche P, Schandene L, Wybran J, Dupont E: High IL-6 serum levels and increased production by leukocytes in alcoholic liver cirrhosis. Correlation with IgA serum levels and lymphokine production. Clin Exp Immunol 77:221–225, 1989PubMedGoogle Scholar
  2. 2.
    Ewald SJ, Shao H: Ethanol increases apoptotic cell death of thymocytes in vitro. Alcohol Clin Exp Res 17:359–365, 1993PubMedGoogle Scholar
  3. 3.
    Jerrels TR, Marietta CA, Eckhardt MJ, Majchrowith E, Weight FF: Effects of ethanol administration on parameters of immunocompetency in rats. J Leuk Biol 39:499–510, 1986Google Scholar
  4. 4.
    Khoruts A, Stahnke L, McClain CJ, Logan G, Allen JI: Circulating tumor necrosis factor, interleukin-1 and interleukin-6 concentrations in chronic alcoholic patients. Hepatology 13:267–276, 1991PubMedGoogle Scholar
  5. 5.
    Meadows GG, Wallendal M, Kosugi A, Wunderlich J, Singer DS: Ethanol induces marked changes in lymphocyte populations and natural killer cell activity in mice. Alcohol Clin Exp Res 16:474–479, 1992PubMedGoogle Scholar
  6. 6.
    Morland B, Morland H: The interaction of ethanol with human monocyte IgG-Fc receptors, characterized by monoclonal antibodies raised against two distinct receptor subpopulations. Scand J Immunol 29:573–577, 1989PubMedGoogle Scholar
  7. 7.
    Nelson S, Bagby GJ, Bainton G, Warren WR: The effects of acute and chronic alcoholism on tumor necrosis factor and inflammatory response. J Infect Dis 1989:422–429, 1989Google Scholar
  8. 8.
    Bermudez LE, Wu M, Martinelli J, Young LS: Ethanol affects release of TNF and GM-CSF and membrane expression of TNF receptors by human macrophages. Lymphokine Cytokine Res 10:413–419, 1991PubMedGoogle Scholar
  9. 9.
    Bermudez LE, Young L: Ethanol augments intracellular survival of Mycobacterium avium complex and impairs macrophage responses to cytokines. J Infect Dis 163:1286–1292, 1991PubMedGoogle Scholar
  10. 10.
    Szabo G, Verma B, Fogarasi M, Catalano D: Induction and modulation of transforming growth factor β and prostaglandin E2 by ethanol in human monocytes. J Leuk Biol 52:602–611, 1992Google Scholar
  11. 11.
    Szabo G, Verma B, Catalano D: Selective inhibition of antigen-specific T lymphocyte proliferation by acute ethanol exposure: The role of impaired monocyte antigen presentation capacity and mediator production. J Leuk Biol 54:534–544, 1993Google Scholar
  12. 12.
    Verma BK, Fogarasi M, Szabo G: Down-regulation of TNFα activity by acute ethanol treatment in human peripheral blood monocytes. J Clin Immunol 13:8–22, 1993PubMedGoogle Scholar
  13. 13.
    Watson RR: Diagnosis of alcohol abuse by modulation of immune responses.In Diagnosis of Alcohol Abuse, R Watson (ed). Boca Raton, FL, CRC Press, 1989, pp 101–106Google Scholar
  14. 14.
    Cook RT, Garvey MJ, Booth BM, Goeken JA, Stewart B, Noel M: Activated CD-8 cells and HLA DR expression in alcoholics without overt liver disease. J Clin Immunol 11:1991Google Scholar
  15. 15.
    Szabo G: Monocyte-mediated immunosuppression after acute ethanol exposure.In Alcohol, Drugs of Abuse and Immunomodulation. RR Watson (ed). Tarrytown, NY, Pergamon Press, 1993, pp 121–133Google Scholar
  16. 16.
    Matsuoka M, Tsukamoto H: Stimulation of hepatic lipocyte collagen production by Kupffer cell-derived transforming growth factor β: Implication for a pathogenetic role in alcoholic liver fibrogenesis. Hepatology 11:599–605, 1990PubMedGoogle Scholar
  17. 17.
    Moscat J, Aracil M, Diez E, Garcia-Barreno P, Municio AM: Effect of ethanol on the arachidonic acid metabolism in mouse peritoneal macrophages. Prostaglandins 34:853–866, 1987PubMedGoogle Scholar
  18. 18.
    Kawakami M, Meyer AA, DeSerres S, Peterson HD: Effects of acute ethanol ingestion and burn injury on serum immunoglobulin. J Burn Care Rehab 11:395–399, 1990Google Scholar
  19. 19.
    Kawakami M, Switzer BR, Herzog SR, Meyer AA: Immune suppression after acute ethanol ingestion and thermal injury. J Surg Res 51:210–215, 1991PubMedGoogle Scholar
  20. 20.
    Miller-Graziano CL, Szabo G, Kodys K, Griffey K: Aberrations in post-trauma monocyte subpopulation: Role in septic shock syndrome. J Trauma 30:S86-S96, 1990PubMedGoogle Scholar
  21. 21.
    Miller-Graziano C, Szabo G, Griffey K, Metha B, Kodys K, Catalano D: Role of elevated MØ TGFβ production in post-trauma immunosuppression. J Clin Immunol 11:95–102, 1991PubMedGoogle Scholar
  22. 22.
    Miller-Graziano C, Szabo G, Kodys K: The interactions of immunopathological mediators (TNF, TGFβ, PGE2) in traumatized individuals.In The Immune Sequences of Trauma, Shock, and Sepsis-Mechanisms and Therapeutic Approaches, E Faist (ed). Berlin, Springer-Verlag, 1992, pp 637–650Google Scholar
  23. 23.
    Faist E, Stork M, Hultner I, Redl H, Ertel W, Waltz A, Schieldberg F: Functional analysis of monocyte activity through synthesis patterns of proinflammatory cytokines and neopterin in patients in surgical intensive care. Surgery 112:562–572, 1992PubMedGoogle Scholar
  24. 24.
    Damas P, Ledoux D, Nys M, Vrindts Y, DeGrotte D, Franchimont P, Lamy M: Cytokine serum level during severe sepsis in human Il-6 as a marker of severity. Ann Surg 215:356–362, 1991Google Scholar
  25. 25.
    Ayala A, Perrin MM, Chaudry IH: Defective macrophage antigen presentation following haemorrhage is associated with the loss of MHC class II antigens. Immunology 70:33–39, 1990PubMedGoogle Scholar
  26. 26.
    Waydhas C, Nast-Kolb D, Jochum M, Trupka A, Lenk S, Fritz H, Schweiberer L: Inflammatory mediators, infections, sepsis, and multiple organ failure after severe trauma. Arch Surg 127:460–467, 1992PubMedGoogle Scholar
  27. 27.
    Casey LC, Balk RA, Bone RC: Plasma cytokine and endotoxin levels correlate with survival in patients with sepsis syndrome. Ann Intern Med 119:771–778, 1993PubMedGoogle Scholar
  28. 28.
    Szabo G, Kodys K, Miller-Graziano CL: Elevated monocyte interleukin-6 (IL-6) production in immunosuppressed trauma patients. I. Role of FcγRI cross-linking stimulation. J Clin Immunol 11:326–335, 1991PubMedGoogle Scholar
  29. 29.
    Jorens P, Van Damme J, De Backer W: Interleukin-8 in the bronchoalveolar lavage fluid from patients with the adult respiratory distress syndrome. Cytokine 4:592–597, 1992PubMedGoogle Scholar
  30. 30.
    Miller-Graziano CL, Fink M, Wu JY, Szabo G, Kodys K: Mechanisms of altered monocyte prostaglandin E2 production in severely injured patients. Arch Surg 123:293–299, 1988PubMedGoogle Scholar
  31. 31.
    Ertel W, Morrisson M, Ayala A: Blockade of prostaglandin production increases cachectin synthesis and prevents depression of macrophage functions after hemorrhagic shock. Ann Surg 213:265–271, 1991PubMedGoogle Scholar
  32. 32.
    Moses T, Ben-Efraim S, Tak C: Serum levels of tumor necrosis factor determine the fatal or nonfatal course of endotoxic shock. Immunol Lett 27:157–162, 1991PubMedGoogle Scholar
  33. 33.
    Takayama TK, Miller C, Szabo G: Elevated tumor necrosis factor production concomitant to elevated prostaglandin E2 production by trauma patients' monocytes. Arch Surg 125:29–35, 1990PubMedGoogle Scholar
  34. 34.
    Wherry JC, Pennington JE, Wenzel RP: Tumor necrosis factor and the therapeutic potential of anti-tumor necrosis factor antibodies. Crit Care Med 21(10):S436-S440, 1993PubMedGoogle Scholar
  35. 35.
    Bodmer M, Fournel MA, Hinshaw LB: Preclinical review of anti-tumor necrosis factor monoclonal antibodies. Crit Care Med 21(10):S441-S446, 1993PubMedGoogle Scholar
  36. 36.
    Roumen RMH, Hendriks T, van der Ven-Jongekrijg J, Nieuwenhuijzen GAP, Sauerwein RW, van der Meer JWM, Goris RJA: Cytokine patterns in patients after major vascular surgery, hemorrhagic shock, and severe blunt trauma. Ann Surg 218(6):769–776, 1993PubMedGoogle Scholar
  37. 37.
    Heideman M, Kaijser B, Gelin LE: Complement activation and hematologic, hemodynamic, and respiratory reactions early after soft tissue injury. J Trauma 18:696–700, 1978PubMedGoogle Scholar
  38. 38.
    Morell V: Predicting severity of trauma by admission white blood cell count, serum potassium level, and arterial pH. South Med J 86:658–659, 1993PubMedGoogle Scholar
  39. 39.
    Chomczynski P, Sacchi N: Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162:156–159, 1987PubMedGoogle Scholar
  40. 40.
    Szabo G, Miller-Graziano CL, Wu J, Takayama T, Kodys K: Differential tumor necrosis factor production by human monocyte subsets. J Leuk Biol 47:206–216, 1990Google Scholar
  41. 41.
    Jacob CO, Lewis GD, HO, McDevitt: MHC ClassII-associated variation in the production of tumor necrosis factor in mice and humans: Relevance to the pathogenesis of autoimmune diseases. Immunol Res 10:156–168, 1991PubMedGoogle Scholar
  42. 42.
    Szabo G, Kodys K, Miller-Graziano CL: Elevated monocyte IL-6 production in immunosuppressed trauma patients. II. Downregulation by IL-4. J Clin Immunol 11:336–344, 1991PubMedGoogle Scholar
  43. 43.
    Spengler RN, Spengler ML, Strieter RM, Remick DG, Larrick JW, Kunkel SL: Modulation of tumor necrosis factor-3α gene expression. J Immunol 142:4346–4350, 1989PubMedGoogle Scholar
  44. 44.
    Dunham DM, Arkins S, Edwards CK, Dantzer R, Kelley KW: Role of Interferon-gamma in counteracting the sup- pressive effects of transforming growth factor-β2 and glucocorticoids on the production of tumor necrosis factor-α. J Leuk Biol 48:473–481, 1990Google Scholar
  45. 45.
    Tracey KJ: Tumor necrosis factor (cachectin) in the biology of septic shock syndrome. Circ Shock 35:123–128, 1991PubMedGoogle Scholar
  46. 46.
    Sharma S, Olchowy T, Yang Z: TNFα and IL-1 enhance LPS-mediated bovine endothelial cell injury. J Leuk Biol 51:579–585, 1992Google Scholar
  47. 47.
    Piquet P, Grau G, Vassali P: TNF and immunopathology. Immunol Res 10:122–140, 1991PubMedGoogle Scholar
  48. 48.
    Goldman G, Welbourn R, Kobzik L: TNFα mediates acid aspiration-induced systemic organ injury. Ann Surg 212:513–520, 1990PubMedGoogle Scholar
  49. 49.
    Karkar A, Koshino Y, Cashman S: Passive immunization against TNFα and IL-1β protects from LPS enhancing glomerular injury in nephrotoxic nephritis in rats. Clin Exp Immunol 90:312–318, 1992PubMedGoogle Scholar
  50. 50.
    Szabo G, Kodys K, Miller-Graziano CL: Dibutyryl-cAMP modulation of receptor expression and antigen presentation capacity in monocyte subpopulations. Int J Immunopharmacol 16(2):151–162, 1994PubMedGoogle Scholar
  51. 51.
    Fukushima R, Gianotti L, Alexander J: The degree of bacterial translocation is a determinant factor for mortality after burn injury and is improved by prostaglandin analogs. Ann Surg 216:438–444, 1992PubMedGoogle Scholar
  52. 52.
    Spengler RN, Spengler ML, Lincoln P, Remick DG, Strieter RM, Kunkel SL: Dynamics of dibutyryl cyclic AMP- and prostaglandin E2-mediated suppression of lipopolysaccharide-induced tumor necrosis factor alpha gene expression. Infect Immun 57:2837–2841, 1989PubMedGoogle Scholar
  53. 53.
    Molloy RG, O'Riordain M, Holzheimer R, Nestor M, Collins K, Mannick JA, Rodrick ML: Mechanism of increased tumor necrosis factor production after thermal injury. J Immunol 151:2142–2149, 1993PubMedGoogle Scholar
  54. 54.
    Spinas GA, Keller U, Brockhaus M: Release of soluble receptors for TNF in relation to circulating TNF during experimental endotoxemia. J Clin Invest 90:533–536, 1992PubMedGoogle Scholar
  55. 55.
    Nii A, Sone S, Orino E: Induction of a 26-kDa membrane form TNFα in human alveolar macrophages. J Leuk Biol 53:29–36, 1993Google Scholar
  56. 56.
    Ayala P, Perrin MM, Wang P: Hemorrhage induces enhanced Kupffer cell cytotoxicity while decreasing peritoneal or splenic macrophage capacity. Involvement of cell-associated tumor necrosis factor and reactive nitrogen. J Immunol 147:4147–4154, 1991PubMedGoogle Scholar
  57. 57.
    Ware CF, Crowe PD, Grayson MH, Androlewich MJ, Briwning JL: Expression of surface lymphotoxin and tumor necrosis factor on activated T, B, and natural killer cells. J Immunol 149:3881–3888, 1992PubMedGoogle Scholar
  58. 58.
    Kappler J, Kotzin B, Herron L, Gelfand E, Bigler R, Boylston A, Carrel S, Posnatt D, Choi Y, Marrack P: V beta-specific stimulation of human T cells by staphylococcal toxins. Science 244:811, 1989PubMedGoogle Scholar
  59. 59.
    See RH, Krystal G, Chow AW: Receptors for toxic shock syndrome toxin-1 and staphylococcal enterotoxin A on human blood monocytes. Can J Microbiol 38:937–944, 1992PubMedGoogle Scholar
  60. 60.
    See RH, Kum WWS, Chang AH, Goh SH, Chow AW: Induction of tumor necrosis factor and interleukin-1 by purified staphylococcal toxic shock syndrome toxin 1 requires the presence of both monocytes and T lymphocytes. Infect Immun 60:2612–2618, 1992PubMedGoogle Scholar
  61. 61.
    Gjorloff A, Fischer H, Hedlung G, Hansson J, Kenney JS, Allison AC, Sjogren HO, Dohlsten M: Induction of interleukin-1 in human monocytes by the superantigen Staphylococcal enterotoxin A requires the participation of T cells. Cell Immunol 137:61–71, 1991PubMedGoogle Scholar
  62. 62.
    Parsonnet J, Gillis ZA: Production of TNF by human monocytes in response to toxic-shock-syndrome toxin-1. J Infect Dis 158:1026–1033, 1988PubMedGoogle Scholar
  63. 63.
    Trede NS, Chantila T, Geha R: AP-1 is stimulated by microbial superantigens in human monocytic cells. Eur J Immunol 23:2129–2135, 1993PubMedGoogle Scholar
  64. 64.
    Palkama T, Hurme M: Signal transduction mechanisms of HLA-DR-mediated interleukin-1β production in human MØ. Hum Immunol 36:259–267, 1993PubMedGoogle Scholar

Copyright information

© Plenum Publishing Corporation 1994

Authors and Affiliations

  • Gyongyi Szabo
    • 1
  • Pranoti Mandrekar
    • 1
  • Bikash Verma
    • 1
  • Ann Isaac
    • 1
  • Donna Catalano
    • 1
  1. 1.Department of SurgeryUniversity of Massachusetts Medical CenterWorcester

Personalised recommendations