Background/Aims: Alcohol use alters inflammatory cell responses. While alcohol has direct effects on pancreatic acinar cells, activation of inflammatory cells is a major component of the pathology of alcoholic pancreatitis. Methods: The effects of acute or chronic alcohol exposure were evaluated in human monocytes on the production of TNFα or IL-10 production, pro-inflammatory gene and nuclear factor-κB (NF-κB) activation. Results: Moderate, acute alcohol consumption or equivalent doses of alcohol in vitro had anti-inflammatory effects on monocyte activation via inhibition of pro-inflammatory genes and NF-κB activation, inhibition of TNFα production and augmentation of the anti-inflammatory cytokine, IL-10. In contrast, acute alcohol treatment augmented NF-κB activation and TNFα production and inhibited IL-10 levels in the presence of complex stimulation with combined TLR2 and TLR4 ligands. Prolonged alcohol exposure also resulted in an increase in NF-κB and TNFα production in response to TLR4 stimulation with LPS. Conclusion: These results suggest that alcohol can either attenuate or promote inflammatory responses that are critical in pancreatitis. Our results support the hypothesis that both acute alcohol intake in the presence of complex stimuli (such as necrotic cells) and chronic alcohol exposure result in hyper-responsiveness of monocytes to inflammatory signals and may contribute to increased inflammation in pancreatitis.
Copyright © 2007 S. Karger AG, Basel and IAP
- Cook RT: Alcohol abuse, alcoholism and damage to the immune system: a review. Alcohol Clin Exp Res 1998;22:1927–1942.
- Naveau S, Raynard B, Ratziu V, Abella A, Imbert-Bismut F, Messous D, Beuzen F, Capron F, Thabut D, Munteanu M, Chaput JC, Poynard T: Biomarkers for the prediction of liver fibrosis in patients with chronic alcoholic liver disease. Clin Gastroenterol Hepatol 2005;3:167–174.
- Jaakola M, Sillanaukee P, Lof K, Koivula T, Nordack I: Amount of alcohol is an important determinant of the severity of acute alcoholic pancreatitis. Surgery 1994;115:31–38.
- Szabo G, Mandrekar P, Dolganiuc A, Catalano D, Kodys K: 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 IFNγ levels. Alcohol Clin Exp Res 2001;25:1766–1772.
- Szabo G, Catalano D, White B, Mandrekar P: Acute alcohol consumption inhibits accessory cell function of monocytes and dendritic cells. Alcohol Clin Exp Res 2004;28:824–828.
- Mandrekar P, Catalano D, Dolganiuc A, Kodys K, Szabo G: Inhibition of myeloid dendritic cell accessory cell function by alcohol correlates with reduced CD80/CD86 expression and decreased IL-12 production. J Immunol 2004;173:3398–3407.
- Takeda K, Akira S: TLRs in innate immunity. Int Immunol 2005;17:1–14.
- Yamamoto M, Akira S: TIR domain-containing adaptors regulate TLR signaling pathways. Adv Exp Med Biol 2005;560:1–9.
- Jarrossay D, Napolitani G, Colonna M, Sallusto F, Lanzavecchia A: Specialization and complementarity in microbial molecule recognition by human myeloid and plasmacytoid dendritic cells. Eur J Immunol 2001;31:3388–3393.
- Wagner H, Bauer S: All is not Toll: new pathways in DNA recognition. J Exp Med 2006;203:265–268.
- Vabulas RM, Ahmad-Nejad P, Ghose S, Kirschning CJ, Issels RD, Wagner H: HSP70 as endogenous stimulus of the Toll/interleukin-1 receptor signal pathway. J Biol Chem 2002;277:15107–15112.
- Ohashi K, Burkart V, Flohe S, Kolb H: Cutting edge: heat shock protein 60 is a putative endogenous ligand of the Toll-like receptor-4 complex. J Immunol 2000;164:558–561.
- Dufour MC, Adamson MD: The epidemiology of alcohol-induced pancreatitis. Pancreas 2003;27:286–290.
- Apte MV, Wilson JS: Alcohol-induced pancreatic injury. Best Pract Res Clin Gastroenterol 2003;17:593–612.
- Schneider A, Singer MV: Alcoholic pancreatitis. Dig Dis 2005;23:222–231.
- Pandol SJ, Gukovsky I, Satoh A, Lugea A, Gukovskaya AS: Emerging concepts for the mechanism of alcoholic pancreatitis from experimental models. J Gastroenterol 2003;38:623–628.
- Apte MV, Pirola RC, Wilson JS: Molecular mechanisms of alcoholic pancreatitis. Dig Dis 2005;23:232–240.
- Somogyi L, Martin S, Venkatesan T, Ulrich C: Recurrent pancreatitis: an algorithmic approach to identification and elimination of initiating factors. Gastroenterology 2001;120:944–952.
- McKim SE, Uesugi T, Raleigh JA, McClain CJ, Arteel GA: Chronic intragastic alcohol exposure causes hypoxia and oxidative stress in the rat pancreas. Arch Biochem Biophys 2003;417:34–43.
- Weber CK, Adler G: From acinar cell damage to systemic inflammatory response: current concepts in pancreatitis. Pancreatology 2001;1:356–362.
- Siegmund SV, Brenner DA: Molecular pathogenesis of alcohol-induced hepatic fibrosis. Alcohol Clin Exp Res 2005;29:102S–109S.
- Verma BK, Fogarsi M, Szabo G: Down-regulation of TNF activity by acute ethanol treatment in human peripheral blood monocytes. J Clin Immunol 1993;13:8–23.
- Mandrekar P, Catalano D, Szabo G: Human monocyte IL-10 production is increased by acute ethanol treatment. Cytokines 1996;8:567–577.
- Szabo G, Chavan S, Mandrekar P, Catalano D: Acute alcohol consumption attenuates IL-8 and MCP-1 induction in response to ex vivo stimulation. J Clin Immunol 1999;19:67–76.
- Szabo G, Mandrekar P, Catalano D: Inhibition of superantigen-induced T cell proliferation and monocyte IL-1β, TNF-α, and IL-6 production by acute ethanol treatment. J Leukoc Biol 1995;58:342–350.
- McClain CJ, Cohen DA: Increased tumor necrosis factor production by monocytes in alcoholic hepatitis. Hepatology 1989;9:349–351.
- McClain CJ, Hill DB, Song Z, Deaciuc I, Barve S: Monocyte activation in alcoholic liver disease. Alcohol 2002;27:53–61.
- Khoruts A, Stahnke L, McClain CJ, Logan G, Allen JI: Circulating tumor necrosis factor, interleukin-1 and interlukin-6 concentrations in chronic alcoholic patients. Hepatology 1991;13:267–276.
- Hill DLB, Marsano LS, McClain CJ: Increased plasma interleukin-8 concentrations in alcoholic hepatitis. Hepatology 1993;18:576–580.
- Pastor CM, Pugin J, Kwak B, Chanson M, Mach F, Hadengue A, Frossard JL: Role of Toll-like receptor 4 on pancreatic and pulmonary injury in a mice model of acute pancreatitis associated with endotoxemia. Crit Care Med. 2004;32:1759–1763.
- Mandrekar P, Catalano D, White B, Szabo G: Moderate alcohol intake in humans attenuates monocyte inflammatory responses: inhibition of NF-3B and induction of IL-10. Alcohol Clin Exp Res 2006;30:135–139.
- Enomoto N, Schemmer P, Ikejima K, Takei Y, Sato N, Brenner DA, Thurman RG: Long-term alcohol exposure changes sensitivity of rat Kupffer cells to lipopolysaccharide. Alcohol Clin Exp Res 2001;25:1360–1367.
- Oak S, Mandrekar P, Szabo G: TLR2 and TLR4-mediated signals determine attenuation or augmentation of inflammation by acute alcohol in monocytes. J Immunol 2006;176:7628–7635.
- Fortunato F, Deng X, Gates LK, McClain CJ, Bimmler D, Graf R, Whitcomb DC: Pancreatic response to endotoxin after chronic alcohol exposure: switch from apoptosis to necrosis? Am J Physiol 2006;290:232–241.
- Bode C, Bode JC: Effect of alcohol consumption on the gut. Best Pract Res Clin Gastroenterol 2003;17: 575–592.
- Thurman RG: II Alcoholic liver injury involves activation of Kupffer cells by endotoxin. Am J Physiol 1998;275:G605–G611.
- Wang X, Wu L, Wu K, Zhang R, Dong Y: Roles of endotoxin-related signaling molecules in the progression of acute necrotizing pancreatitis in mice. Pancreas 2005;31:251–257.
- Cario E, Golenbock DT, Visintin A, Runzi M, Gerken G, Podolsky DK: Trypsin-sensitive modulation of intestinal epithelial MD-2 as mechanism of lipopolysaccharide tolerance. J Immunol. 2006 1;176:4258–4266.
- Wang P, Wu P, Siegel MI, Egan RW, Billah MM: IL-10 inhibits transcription of cytokine genes in human peripheral blood mononuclear cells. J Immunol 1994;153:811–816.
- Pedersen N, Larsen S, Seidelin JB, Nielsen OH: Alcohol modulates circulating levels of Interleukin-6 and monocyte chemoattractant protein-1 in chronic pancreatitis. Scand J Gastroenterol 2004;3:277–282.
- Gukovsky I, Gukovskaya AS, Blinman TA, Zaninovic V, Pandol SJ: Early NF-kappaB activation is associated with hormone-induced pancreatitis. Am J Physiol 1998;275:G1402–G1414.
- Vacquero E, Gukovsky I, Zaninovic V, Gukovskaya AS, Pandol SJ: Localized pancreatic NF-kappaB activation and inflammatory response in taurocholate-induced pancreatitis. Am J Physiol 2001;280:G1197–G1208.
- Hosseini S, Gukovskaya A, Cheng J, Gukosky I, Pandol S: Ethanol potentiates cholecystokinin-induced but inhibits thapsigargin-induced NFκB activation in pancreatic acinar cells (abstract). Gastroenterology 2002;122:A-282.
- Deng X, Wang L, Elm MS, Gabazadeh D, Diorio GJ, Eagon PK, Whitcomb DC: Chronic alcohol consumption accelerates fibrosis in response to caerulein-induced pancreatitis in rats. Am J Pathol 2005;166:93–106.
- Szabo G, Verma BK, Fogarasi M, Catalano D: Induction of transforming growth factor-beta and prostaglandin E2 production by ethanol in human monocytes. J Leuk Biol 1992;52:602–610.
Gyongyi Szabo, MD, PhD
Hepatology and Liver Center, Department of Medicine
University of Massachusetts Medical Center, 364 Plantation Street LRB125
Worcester, MA 01605 (USA)
Tel. +1 508 856 5275 Fax +1 508 856 4770, E-Mail firstname.lastname@example.org
Published online: June 21, 2007
Number of Print Pages : 9
Number of Figures : 7, Number of Tables : 0, Number of References : 45
Vol. 7, No. 2-3, Year 2007 (Cover Date: July 2007)
Journal Editor: Urrutia, R. (Rochester, Minn.)
ISSN: 1424–3903 (print), 1424–3911 (Online)
For additional information: http://www.karger.com/PAN
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.