期刊论文详细信息
BMC Medicine
Interleukin-22 predicts severity and death in advanced liver cirrhosis: a prospective cohort study
Heiko Mühl2  Albrecht Piiper3  Stefan Zeuzem3  Josef Pfeilschifter2  Eva Herrmann1  Oliver Waidmann3  Natalie Filmann1  Lisa Kapper3  Friederike Brunner3  Malte Bachmann2  Ina Rudloff2  Bernd Kronenberger3 
[1] Institut für Biostatistik und mathematische Modellierung, Klinikum der J.W. Goethe Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany;Pharmazentrum Frankfurt, Klinikum der J.W. Goethe Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany;Medizinische Klinik 1, Klinikum der J.W. Goethe Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany
关键词: MELD;    Alcoholic liver disease;    Hepatitis;    Liver-related complications;    Liver cirrhosis;    Interleukin-22;   
Others  :  857355
DOI  :  10.1186/1741-7015-10-102
 received in 2012-03-20, accepted in 2012-09-11,  发布年份 2012
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【 摘 要 】

Background

Interleukin-22 (IL-22), recently identified as a crucial parameter of pathology in experimental liver damage, may determine survival in clinical end-stage liver disease. Systematic analysis of serum IL-22 in relation to morbidity and mortality of patients with advanced liver cirrhosis has not been performed so far.

Methods

This is a prospective cohort study including 120 liver cirrhosis patients and 40 healthy donors to analyze systemic levels of IL-22 in relation to survival and hepatic complications.

Results

A total of 71% of patients displayed liver cirrhosis-related complications at study inclusion. A total of 23% of the patients died during a mean follow-up of 196 ± 165 days. Systemic IL-22 was detectable in 74% of patients but only in 10% of healthy donors (P < 0.001). Elevated levels of IL-22 were associated with ascites (P = 0.006), hepatorenal syndrome (P < 0.0001), and spontaneous bacterial peritonitis (P = 0.001). Patients with elevated IL-22 (>18 pg/ml, n = 57) showed significantly reduced survival compared to patients with regular (≤18 pg/ml) levels of IL-22 (321 days versus 526 days, P = 0.003). Other factors associated with reduced overall survival were high CRP (≥2.9 mg/dl, P = 0.005, hazard ratio (HR) 0.314, confidence interval (CI) (0.141 to 0.702)), elevated serum creatinine (P = 0.05, HR 0.453, CI (0.203 to 1.012)), presence of liver-related complications (P = 0.028, HR 0.258, CI (0.077 to 0.862)), model of end stage liver disease (MELD) score ≥20 (P = 0.017, HR 0.364, CI (0.159 to 0.835)) and age (P = 0.011, HR 0.955, CI (0.922 to 0.989)). Adjusted multivariate Cox proportional-hazards analysis identified elevated systemic IL-22 levels as independent predictors of reduced survival (P = 0.007, HR 0.218, CI (0.072 to 0.662)).

Conclusions

In patients with liver cirrhosis, elevated systemic IL-22 levels are predictive for reduced survival independently from age, liver-related complications, CRP, creatinine and the MELD score. Thus, processes that lead to a rise in systemic interleukin-22 may be relevant for prognosis of advanced liver cirrhosis.

【 授权许可】

   
2012 Kronenberger et al; licensee BioMed Central Ltd.

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【 参考文献 】
  • [1]European Association for the Study of the Liver: EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol 2010, 53:397-417.
  • [2]Dumoutier L, Louahed J, Renauld JC: Cloning and characterization of IL-10-related T cell-derived inducible factor (IL-TIF), a novel cytokine structurally related to IL-10 and inducible by IL-9. J Immunol 2000, 164:1814-1819.
  • [3]Wolk K, Witte E, Witte K, Warszawska K, Sabat R: Biology of interleukin-22. Semin Immunopathol 2010, 32:17-31.
  • [4]Sonnenberg GF, Fouser LA, Artis D: Border patrol: regulation of immunity, inflammation and tissue homeostasis at barrier surfaces by IL-22. Nat Immunol 2011, 12:383-390.
  • [5]Lafdil F, Miller AM, Ki SH, Gao B: Th17 cells and their associated cytokines in liver diseases. Cell Mol Immunol 2010, 7:250-254.
  • [6]Wolk K, Witte E, Wallace E, Döcke W, Kunz S, Asadullah K, Volk H, Sterry W, Sabat R: IL-22 regulates the expression of genes responsible for antimicrobial defense, cellular differentiation, and mobility in keratinocytes: a potential role in psoriasis. Eur J Immunol 2006, 36:1309-1323.
  • [7]Andoh A, Zhang Z, Inatomi O, Fujino S, Deguchi Y, Araki Y, Tsujikawa T, Kitoh K, Kim-Mitsuyama S, Takayanagi A, Shimizu N, Fujiyama Y: Interleukin-22, a member of the IL-10 subfamily, induces inflammatory responses in colonic subepithelial myofibroblasts. Gastroenterology 2005, 129:969-984.
  • [8]Ikeuchi H, Kuroiwa T, Hiramatsu N, Kaneko Y, Hiromura K, Ueki K, Nojima Y: Expression of interleukin-22 in rheumatoid arthritis: potential role as a proinflammatory cytokine. Arthritis Rheum 2005, 52:1037-1046.
  • [9]Bingold TM, Ziesché E, Scheller B, Sadik CD, Franck K, Just L, Sartorius S, Wahrmann M, Wissing H, Zwissler B, Pfeilschifter J, Mühl H: Interleukin-22 detected in patients with abdominal sepsis. Shock 2010, 34:337-340.
  • [10]Missé D, Yssel H, Trabattoni D, Oblet C, Lo Caputo S, Mazzotta F, Pène J, Gonzalez J, Clerici M, Veas F: IL-22 participates in an innate anti-HIV-1 host-resistance network through acute-phase protein induction. J Immunol 2007, 178:407-415.
  • [11]Liang SC, Nickerson-Nutter C, Pittman DD, Carrier Y, Goodwin DG, Shields KM, Lambert A, Schelling SH, Medley QG, Ma H, Collins M, Dunussi-Joannopoulos K, Fouser LA: IL-22 induces an acute-phase response. J Immunol 2010, 185:5531-5538.
  • [12]Ma H, Liang S, Li J, Napierata L, Brown T, Benoit S, Senices M, Gill D, Dunussi-Joannopoulos K, Collins M, Nickerson-Nutter C, Fouser LA, Young DA: IL-22 is required for Th17 cell-mediated pathology in a mouse model of psoriasis-like skin inflammation. J Clin Invest 2008, 118:597-607.
  • [13]Geboes L, Dumoutier L, Kelchtermans H, Schurgers E, Mitera T, Renauld J, Matthys P: Proinflammatory role of the Th17 cytokine interleukin-22 in collagen-induced arthritis in C57BL/6 mice. Arthritis Rheum 2009, 60:390-395.
  • [14]Zheng Y, Valdez PA, Danilenko DM, Hu Y, Sa SM, Gong Q, Abbas AR, Modrusan Z, Ghilardi N, de Sauvage FJ, Ouyang W: Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat Med 2008, 14:282-289.
  • [15]Aujla SJ, Chan YR, Zheng M, Fei M, Askew DJ, Pociask DA, Reinhart TA, McAllister F, Edeal J, Gaus K, Husain S, Kreindler JL, Dubin PJ, Pilewski JM, Myerburg MM, Mason CA, Iwakura Y, Kolls JK: IL-22 mediates mucosal host defense against Gram-negative bacterial pneumonia. Nat Med 2008, 14:275-281.
  • [16]Sugimoto K, Ogawa A, Mizoguchi E, Shimomura Y, Andoh A, Bhan AK, Blumberg RS, Xavier RJ, Mizoguchi A: IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J Clin Invest 2008, 118:534-544.
  • [17]Ziesché E, Bachmann M, Kleinert H, Pfeilschifter J, Mühl H: The interleukin-22/STAT3 pathway potentiates expression of inducible nitric-oxide synthase in human colon carcinoma cells. J Biol Chem 2007, 282:16006-16015.
  • [18]Mühl H, Bachmann M, Pfeilschifter J: Inducible NO synthase and antibacterial host defence in times of Th17/Th22/T22 immunity. Cell Microbiol 2011, 13:340-348.
  • [19]Hoegl S, Bachmann M, Scheiermann P, Goren I, Hofstetter C, Pfeilschifter J, Zwissler B, Muhl H: Protective properties of inhaled IL-22 in a model of ventilator-induced lung injury. Am J Respir Cell Mol Biol 2011, 44:369-376.
  • [20]Radaeva S, Sun R, Pan H, Hong F, Gao B: Interleukin 22 (IL-22) plays a protective role in T cell-mediated murine hepatitis: IL-22 is a survival factor for hepatocytes via STAT3 activation. Hepatology 2004, 39:1332-1342.
  • [21]Zenewicz LA, Yancopoulos GD, Valenzuela DM, Murphy AJ, Karow M, Flavell RA: Interleukin-22 but not interleukin-17 provides protection to hepatocytes during acute liver inflammation. Immunity 2007, 27:647-659.
  • [22]Ki SH, Park O, Zheng M, Morales-Ibanez O, Kolls JK, Bataller R, Gao B: Interleukin-22 treatment ameliorates alcoholic liver injury in a murine model of chronic-binge ethanol feeding: role of signal transducer and activator of transcription 3. Hepatology 2010, 52:1291-1300.
  • [23]Jiang R, Tan Z, Deng L, Chen Y, Xia Y, Gao Y, Wang X, Sun B: Interleukin-22 promotes human hepatocellular carcinoma by activation of STAT3. Hepatology 2011, 54:900-909.
  • [24]Zhang Y, Cobleigh MA, Lian J, Huang C, Booth CJ, Bai X, Robek MD: A proinflammatory role for interleukin-22 in the immune response to hepatitis B virus. Gastroenterology 2011, 141:1897-1906.
  • [25]Dambacher J, Beigel F, Zitzmann K, Heeg MHJ, Göke B, Diepolder HM, Auernhammer CJ, Brand S: The role of interleukin-22 in hepatitis C virus infection. Cytokine 2008, 41:209-216.
  • [26]Park O, Wang H, Weng H, Feigenbaum L, Li H, Yin S, Ki SH, Yoo SH, Dooley S, Wang F, Young HA, Gao B: In vivo consequences of liver-specific interleukin-22 expression in mice: Implications for human liver disease progression. Hepatology 2011, 54:252-261.
  • [27]Leipe J, Schramm MA, Grunke M, Baeuerle M, Dechant C, Nigg AP, Witt MN, Vielhauer V, Reindl CS, Schulze-Koops H, Skapenko A: Interleukin 22 serum levels are associated with radiographic progression in rheumatoid arthritis. Ann Rheum Dis 2011, 70:1453-1457.
  • [28]Córdoba J: New assessment of hepatic encephalopathy. J Hepatol 2011, 54:1030-1040.
  • [29]Pickert G, Neufert C, Leppkes M, Zheng Y, Wittkopf N, Warntjen M, Lehr H, Hirth S, Weigmann B, Wirtz S, Ouyang W, Neurath MF, Becker C: STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. J Exp Med 2009, 206:1465-1472.
  • [30]Xing W, Zou M, Liu S, Xu T, Gao J, Wang J, Xu D: Hepatoprotective effects of IL-22 on fulminant hepatic failure induced by d-galactosamine and lipopolysaccharide in mice. Cytokine 2011, 56:174-179.
  • [31]Ren X, Hu B, Colletti LM: IL-22 is involved in liver regeneration after hepatectomy. Am J Physiol Gastrointest Liver Physiol 2010, 298:74-80.
  • [32]Lavoie TN, Stewart CM, Berg KM, Li Y, Nguyen CQ: Expression of interleukin-22 in Sjögren's syndrome: significant correlation with disease parameters. Scand J Immunol 2011, 74:377-382.
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