Cellular and Cytokine-Mediated Mechanisms of Inflammation and its Modulation in Immune-Mediated Liver Injury

Zusammenfassung

Bei Hepatitisvirusinfektion oder Autoimmunhepatitis wird eine Leberschädigung durch die Immunantwort gegenüber den Fremd- oder Autoantigenen ausgelöst. In letzter Zeit mehren sich Hinweise, dass auch bei toxischer Leberschädigung, bei der die Immunantwort gegen spezifische Leberantigene zunächst nicht im Vordergrund steht, Immunzellen der angeborenen und adaptiven Immunantwort an der Schadensvermittlung beteiligt sind. Zu diesen Erkrankungen gehören unter anderem die Alkoholhepatitis, die nichtalkoholische Steatohepatitis sowie Ischämie/Reperfusionsschäden bei Lebertransplantationen. Hier kann es zu einer Funktionseinbuße der gastrointestinalen Barriere und damit zu einer Zunahme von Bakterien und ihren Toxinen im Pfortaderblut kommen. Bakterielle Toxine können Zellen der angeborenen Immunabwehr wie die Kupfferzellen oder auch konventionelle T-Zellen aktivieren. Vor kurzem konnte gezeigt werden, dass bei Fettleber die invarianten natürlichen Killer-T-Zellen (NKT-Zellen), die spezifisch Glykolipidantigene erkennen, beim Fortschreiten der Erkrankung involviert sind. Sowohl bei nichtalkoholischer Steatohepatitis als auch bei Ischämie/Reperfusionsschädigung beobachtet man das Zytokinprofil einer sogenannten Th1-Immunantwort, die insbesondere durch erhöhte IFNγ- und TNFα-Spiegel gekennzeichnet ist. An der Auslösung dieser Zytokinantwort scheinen NKT-Zellen sowie konventionelle CD4⁺-T-Lymphozyten beteiligt zu sein. Detaillierte Studien der pathophysiologischen Mechanismen einer immunvermittelten Leberschädigung wurden im Modell der Concanavalin A-induzierten Hepatitis durchgeführt. Hierbei wurden nicht nur Immuneffektormechanismen und Zytokinsignaltransduktionswege, die zu Organschädigung, hepatozellulärer Apoptose, Apoptosehemmung und Regeneration führen, sondern seit kurzem auch Mechanismen der Immuntoleranz untersucht. Die tolerogene Funktion der Leber scheint deshalb von besonderer Bedeutung zu sein, da das Organ kontinuierlich Abwehr- und Scavengerfunktionen gegenüber Fremdmaterial aus dem Darm ausüben muss, ohne dass eine chronische Entzündung entsteht.

Abstract

The immune response to foreign or self antigens mediates liver damage during viral or autoimmune hepatitis. However, it now appears that also specific antigen-independent liver diseases, where liver damage has been attributed to occur from oxygen radical formation, seem to be mediated by cells of the innate and adaptive immune response. These liver disorders include alcoholic liver disease, non-alcoholic fatty liver disease or non-alcoholic steatohepatitis, and ischemia/reperfusion injury that impairs the function of liver grafts. Here it seems that breakdown of the gastrointestinal barrier might increase the concentration of bacterial toxins in the portal blood, which then activate cells of the innate immune system, e. g., Kupffer cells, but, depending on the nature of the toxin, probably also conventional T cells. Invariant NKT cells which specifically recognize glycolipid antigens were supposed to become activated during metabolic disorders related to obesity. However, both steatohepatitis as well as ischemia/reperfusion injury are associated with a Th1 cytokine response characterized by IFNγ and TNFα elevation, that might reflect an NKT cell response on the one hand, but also conventional T lymphocytes, in particular CD4⁺ T cells, are critical for the pathophysiology of these disorders. In 1992 we described a model of T cell-dependent liver injury inducible by the T cell-mitogenic lectin concanavalin A. This model of immune-mediated liver injury was intensively used to study pathophysiological immune effector mechanisms as well as cytokine signaling important for hepatocellular apoptosis, inhibition of apoptosis and regeneration. Recently it became evident that the inflammatory response in this model is regulated by specific cytokine signals as well as by immune regulator cells. The immune-regulatory functions of the liver are of particular interest with respect to the scavenger function of this organ, being continuously exposed to foreign antigenic material from the gut which should be eliminated without causing chronic disease.

Schlüsselwörter

Con A-Hepatitis - Leberimmunologie - NKT-Zellen - Th1-Zytokinantwort - Fettleber

Key words

Con A hepatitis - liver immunology - NKT cells - Th1 cytokine response - fatty liver

References

• 1 Schümann J, Tiegs G. Pathophysiological mechanisms of TNF during intoxication with natural or man-made toxins.  Toxicology. 1999;  138 103-126
• 2 Kirillova I, Chaisson M, Fausto N. Tumor necrosis factor Induces DNA replication in hepatic cells through nuclear factor κB activation.  Cell Growth & Diff. 1999;  10 819-828
• 3 Yamada Y, Webber E M, Kirillova I. et al . Analysis of liver regeneration in mice lacking type 1 or type 2 tumor necrosis factor receptor: Requirement for type 1 but not type 2 receptor.  Hepatology. 1998;  28 959-970
• 4 Teoh N C, Farrell G C. Hepatic ischemia reperfusion injury: Pathogenic mechanisms and basis for hepatoprotection.  J Gastroenterol Hepatol. 2003;  18 891-902
• 5 Guidotti L G, Matzke B, Schaller H. et al . High-level hepatitis B virus replication in transgenic mice.  J Virol. 1995;  69 6158-6169
• 6 Pietschmann T, Bartenschlager R. Tissue culture and animal models for hepatitis C virus.  Clin Liver Dis. 2003;  7 23-43
• 7 Sprinzl M F, Oberwinkler H, Schaller H. et al . Transfer of hepatitis B virus genome by adenovirus vectors into cultured cells and mice: crossing the species barrier.  J Virol. 2001;  75 5108-5118
• 8 Sprinzl M, Dumortier J, Protzer U. Construction of recombinant adenoviruses that produce infectious hepatitis B virus.  Methods Mol Med. 2004;  96 209-218
• 9 Hines I N, Wheeler M D. Recent advances in alcoholic liver disease III. Role of the innate immune response in alcoholic hepatitis.  Am J Physiol Gastrointest Liver Phasiol. 2004;  287 G310-G314
• 10 Guebre-Xabier M, Yang S, Kin H Z. et al . Altered hepatic lymphocyte subpopulations in obesity-related murine fatty livers: potential mechanism for sensitization to liver damage.  Hepatology. 2000;  31 633-640
• 11 Li Z, Soloski M J, Diehl A M. Dietary factors alter hepatic innate immune system in mice with nonalcoholic fatty liver disease.  Hepatology. 2005;  42 880-885
• 12 Matarese G, Moschos S, Mantozoros C S. Leptin in immunology.  J Immunol. 2005;  173 3137-3142
• 13 Trayhurn P, Wood I S. Signalling role of adipose tissue: adipokines and inflammation in obesity.  Biochemical Society Transactions. 2005;  33 1078-1081
• 14 Fondevila C, Busuttil R W, Kupiec-Weglinski J W. Hepatic ischemia/reperfusion injury - a fresh look.  Exp Mol Pathol. 2003;  74 86-93
• 15 Zwacka R M, Zhang Y, Halldorson J. et al . CD4 + T-lymphocytes mediate ischemia/reperfusion-induced inflammatory response in mouse liver.  J Clin Invest. 1997;  100 279-289
• 16 Shimamura K, Kawamura H, Nagura T. et al . Association of NKT cells and granulocytes with liver injury after reperfusion of the portal vein.  Cell Immunol. 2005;  234 31-38
• 17 Lohse A W, Manns M, Dienes H P. et al . Experimental autoimmune hepatitis: disease induction, time course and T-cell reactivity.  Hepatology. 1990;  11 24-30
• 18 Lapierre P, Djilali-Saiah I, Vitozzi S. et al . A murine model of type 2 autoimmune hepatitis: Xenoimmunization with human antigens.  Hepatology. 2004;  39 1066-1074
• 19 Tiegs G, Hentschel J, Wendel A. A T-cell dependent experimental liver injury in mice inducible by concanavalin A.  J Clin Invest. 1992;  90 196-203
• 20 Osman Y, Kawamura T, Naito T. et al . Activation of hepatic NKT cells and subsequent liver injury following administration of α-galactosylceramide.  Eur J Immunol. 2000;  30 1919-1928
• 21 Biburger M, Tiegs G. α-Galactosylceramide-induced liver injury in mice is mediated by TNF-α but independent of Kupffer cells.  J Immunol. 2005;  175 1540-1550
• 22 Tiegs G. T Cells, NKT Cells and NK Cells in an Experimental Model of Autoimmune Hepatitis. Gershwin ME, Vierling JM, Manns MP Textbook on Liver Immunology Published in a book; 2003: 171-183
• 23 Cao Q, Batey R, Pang G. et al . IL-6, IFNγ and TNFα production by liver-associated T cells and acute liver injury in rats administered concanavalin A.  Immunol Cell Biol. 1998;  76 542-549
• 24 Leist M, Wendel A. A novel mechanism of murine hepatocyte death inducible by concanavalin A.  J Hepatol. 1996;  25 948-959
• 25 Sass G, Heinlein S, Agli A. et al . Cytokine expression in three mouse models of experimental hepatitis.  Cytokine. 2002;  19 115-120
• 26 Kaneko Y, Harada M, Kawano T. et al . Augmentation of Vα 14 NKT cell-mediated cytotoxicity by interleukin 4 in an autocrine mechanism resulting in the development of concanavalin A-induced hepatitis.  J Exp Med. 2000;  191 105-114
• 27 Gantner F, Leist M, Lohse A W. et al . Concanavalin A-induced T cell-mediated hepatic injury in mice: the role of tumor necrosis factor.  Hepatology. 1995;  21 190-198
• 28 Satoh M, Kobayashi K, Ishii M. et al . Midzonal necrosis of the liver after concanavalin A-injection.  Tohoku J Exp Med. 1996;  180 139-152
• 29 Bowen D G, McCaughan G W, Bertolino P. Intrahepatic immunity: a tale of two sites?.  Trends Immunol. 2005;  26 512-517
• 30 Bowen D G, Warren A, Davis T. et al . Cytokine-dependent bystander hepatitis due to intrahepatic murine CD8⁺ T-cell activation by bone marrow-derived cells.  Gastroenterology. 2002;  123 1252-1264
• 31 Mizuhara H, O’Neill E, Seki N. et al . T cell activation-associated hepatic injury: mediation by tumor necrosis factors and protection by interleukin 6.  J Exp Med. 1994;  179 1529-1537
• 32 Wolf D, Hallmann R, Sass G. et al . TNF-α-induced expression of adhesion molecules in the liver is under the control of tumor necrosis factor receptor 1 - relevance for murine hepatitis.  J Immunol. 2001;  166 1300-1307
• 33 Streetz K, Fregien B, Plümpe J. et al . Dissection of the intracellular pathways in hepatocytes reveals a direct role of Jun Kinase and IRF-1 in Con A-induced liver failure.  J Immunol. 2001;  167 514-523
• 34 Klugewitz K, Adams D H, Emoto M. et al . The composition of intrahepatic lymphocytes: shaped by selective recruitment?.  Trends Immunol. 2004;  25 590-594
• 35 Schümann J, Wolf D, Pahl A. et al . Importance of Kupffer cells for T cell-dependent liver injury in mice.  Am J Pathol. 2000;  157 1671-1683
• 36 Ajuebor M N, Hogaboam C M, Le T. et al . CCL3/MIP-1α is pro-inflammatory in murine T cell-mediated hepatitis by recruiting CCR1-expressing CD4⁺ T cells to the liver.  Eur J Immunol. 2004;  34 2907-2918
• 37 Knolle P A, Gerken G, Löser E. et al . Role of sinusoidal endothelial cells of the liver in concanavalin A-induced hepatic injury in mice.  Hepatology. 1996;  24 824-829
• 38 Lohse A W, Knolle P A, Bilo K. et al . Antigen-presenting function and B7 expression of murine sinusoidal endothelial cells and Kupffer cells.  Gastroenterology. 1996;  110 1175-1181
• 39 Keren Z, Berke G. Selective binding of concanavalin A to target cell major histocompatibility antigens is required to induce non-specific conjugation and lysis by cytolytic T lymphocytes in lectin-dependent cytotoxicity.  Cell Immunol. 1984;  89 458-477
• 40 Sass G, Heinlein S, Agli A. et al . Cytokine expression in three mouse models of experimental hepatitis.  Cytokine. 2002;  19 115-120
• 41 Bonder C S, Ajuebor M N, Zbytnuik L D. et al . Essential role for neutrophil recruitment to the liver in concanavalin A-induced hepatitis.  J Immunol. 2004;  172 45-53
• 42 Massaguer A, Perez-del-Pulgar S, Engel P. et al . Concanavalin A-induced liver injury is severely impaired in mice deficient in P-selection.  J Leukocyte Biol. 2002;  72 262-270
• 43 Khandoga A, Hanschen M, Kesler J S. et al . CD4⁺ T cells contribute to postischemic liver injury in mice by interacting with sinusoidal endothelium and platelets.  Hepatology. 2006;  43 306-315
• 44 Chen D, McKallip R J, Zeytun A. et al . CD44-deficient mice exhibit enhanced hepatitis after concanavalin A injection: evidence for involvement of CD44 in activation-induced cell death.  J Immunol. 2001;  166 5889-5897
• 45 Erhardt A, Biburger M, Papadopoulos T. et al . IL-10, regulatory T cells and Kupffer cells mediate tolerance in concanavalin A-induced liver injury in mice.  Hepatology. in press; 
• 46 Fontenot J D, Rudensky A Y. A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor FoxP3.  Nat Immunol. 2005;  6 331-337
• 47 Crispe I N. Hepatic T cells and liver tolerance.  Nat Rev Immunol. 2003;  3 51-62
• 48 Mizuhara H, Kuno M, Seki N. et al . Strain difference in the induction of T-cell activation-associated, interferon γ-dependent hepatic injury in mice.  Hepatology. 1998;  27 513-519
• 49 Markowitz H, Person D A, Gitnick G L. et al . Immunosuppressive activity of concanavalin A.  Science. 1969;  163 476
• 50 Godfrey D I, Kronenberg M. Going both ways: immune regulation via CD1d-dependent NKT cells.  J Clin Invest. 2004;  114 1379-1388
• 51 Van Kaer L. Regulation of immune responses by CD1d-restricted natural killer T cells.  Immunol Res. 2004;  30 139-153
• 52 Takeda K, Hayakawa Y, Van Kaer L. et al . Critical contribution of liver natural killer T cells to a murine model of hepatitis.  Proc Natl Acad Sci USA. 2000;  97 5498-5503
• 53 Nakagawa R, Nagafune I, Tazunoki Y. et al . Mechanisms of the antimetastatic effect in the liver and of the hepatocyte injury induced by α-galactosylceramide in mice.  J Immunol. 2001;  166 6578-6584
• 54 Küsters S, Gantner F, Künstle G. et al . Interferon-γ plays a critical role in T cell-dependent liver injury in mice initiated by concanavalin A.  Gastroenterology. 1996;  111 462-471
• 55 Parekh V V, Wilson M T, Olivares-Villagómez D. et al . Glycolipid antigen induces long-term natural killer T cell anergy in mice.  J Clin Invest. 2005;  115 2572-2583
• 56 Sakaguchi S. Naturally arising CD4⁺ regulatory T cells for immunologic self-tolerance and negative control of immune responses.  Annu Rev Immunol. 2004;  22 531-562
• 57 Biburger M, Tiegs G. A single treatment with α-galactosylceramide causes activation-induced nonresponsiveness of murine NKT cells and results in tolerance against NKT-mediated liver injury.  Immunobiol. 2005;  210 505
• 58 Küsters S, Tiegs G, Alexopoulou L. et al . In vivo evidence for a functional role of both TNF receptors and transmembrane TNF in experimental hepatitis.  Eur J Immunol. 1997;  27 2870-2875
• 59 Solorzano C C, Ksontini R, Pruitt J H. et al . Involvement of 26-kDa cell-associated TNFα in experimental hepatitis and exacerbation of liver injury with a matrix metalloproteinase inhibitor.  J Immunol. 1997;  58 414-419
• 60 Mizuhara H, Uno M, Seki N. et al . Critical involvement of interferon γ in the pathogenesis of T-cell activation-associated hepatitis and regulatory mechanisms of interleukin-6 for the manifestations of hepatitis.  Hepatology. 1996;  23 1608-1615
• 61 Nicoletti F, Di Marco R, Zaccone P. et al . Murine concanavalin A-induced hepatitis is prevented by interleukin 12 (IL-12) antibody and exacerbated by exogenous IL-12 through an interferon-γ-dependent mechanism.  Hepatology. 2000;  32 728-733
• 62 Faggioni R, Jones-Carson J, Reed D A. et al . Leptin-deficient (ob/ob) mice are protected from T cell-mediated hepatotoxicity: role of tumor necrosis factor (and IL-18.  Proc Natl Acad Sci USA. 2000;  97 2367-2372
• 63 Toyabe S, Seki S, Iiai T. et al . Requirement of IL-4 and liver NK1⁺ T cells for concanavalin A-induced hepatic injury in mice.  J Immunol. 1997;  159 1537-1542
• 64 Tagawa Y, Matthys P, Heremans H. et al . Bimodal role of endogenous interleukin-6 in concanavalin A-induced hepatitis in mice.  J Leukoc Biol. 2000;  67 90-96
• 65 Bozza M, Bliss J L, Maylor R. et al . Interleukin-11 reduces T-cell-dependent experimental liver injury in mice.  Hepatology. 1999;  30 1441-1447
• 66 Louis H, Le Moine O, Peny M O. et al . Production and role of interleukin-10 in concanavalin A-induced hepatitis in mice.  Hepatology. 1997;  25 1382-1389
• 67 Fotin-Mleczek M, Henkler F, Samel D. et al . Apoptotic crosstalk of TNF receptors: TNF-R2-induces depletion of TRAF2 and IAP proteins and accelerates TNF-R1-dependent activation of caspase-8.  J Cell Sci. 2002;  115 2757-2770
• 68 Maeda S, Chang L, Li Z W. et al . IKKβ is required for prevention of apoptosis mediated by cell-bound but not by circulating TNFα.  Immunity. 2003;  19 725-737
• 69 Schümann J, Mühlen K, Kiemer A K. et al . Parenchymal, but not leukocyte, TNFR2 mediates T cell-dependent hepatitis in mice.  J Immunol. 2003;  170 2129-2137
• 70 Koerber K, Sass G, Kiemer A K. et al . In vivo regulation of inducible NO-synthase in immune-mediated liver injury in mice.  Hepatology. 2002;  36 1061-1069
• 71 Song E, Lee S K, Wang J. et al . RNA interference targeting Fas protects mice from fulminant hepatitis.  Nature Med. 2003;  9 347-351
• 72 Descamps D, Vigant F, Esselin S. et al . Expression of non-signaling membrane-anchored death receptors protects murine livers in different models of hepatitis.  Hepatology. 2006;  44 399-409
• 73 Costelli P, Aoki P, Zingaro B. et al . Mice lacking TNFα receptors 1 and 2 are resistant to death and fulminant liver injury induced by agonistic anti-Fas antibody.  Cell Death Differ. 2003;  10 997-1004
• 74 Zheng S J, Wang P, Tsabary G. et al . Critical roles of TRAIL in hepatic cell death and hepatic inflammation.  J Clin Invest. 2004;  113 58-64
• 75 Anand S, Wang P, Yoshimura K. et al . Essential role of TNF family molecule LIGHT as a cytokine in the pathogenesis of hepatitis.  J Clin Invest. 2006;  116 1045-1051
• 76 Hong F, Jaruga B, Kim W H. et al . Oposing roles of STAT1 and STAT3 in T cell-mediated hepatitis: regulation by SOCS.  J Clin Invest. 2002;  110 1503-1513
• 77 Siebler J, Wirtz S, Klein S. et al . A key pathogenic role fort he STAT1/T-bet signaling pathway in T-cell-mediated liver inflammation.  Hepatology. 2003;  38 1573-1580
• 78 Senaldi G, Shaklee C L, Gou J. et al . Protection against the mortality associated with disease models mediated by TNF and IFNγ in mice lacking IFN regulatory factor-1.  J Immunol. 1999;  163 6820-6826
• 79 Kato A, Yoshidome H, Edwards M J. et al . Regulation of liver inflammatory injury by signal transducer and activator of transcription-6.  Am J Pathol. 2000;  157 297-302
• 80 Jaruga B, Hong F H, Sun R. et al . Crucial role of IL-4/STAT6 in T cell-mediated hepatitis: up-regulating eotaxins and IL-5 and recruiting leukocytes.  J Immunol. 2003;  171 3233-3244
• 81 Louis H, Le Moine A, Flamand V. et al . Critical role of interleukin 5 and eosinophils in concanavalin A-induced hepatitis in mice.  Gastroenterology. 2002;  122 2001-2010
• 82 Gao B. Cytokines, STATs and liver disease.  Cell Mol Immunol. 2005;  2 92-100
• 83 Klein C, Wüstefeld T, Assmus U. et al . The IL-6-gp130-STAT3 pathway in hepatocytes triggers liver protection in T cell-mediated liver injury.  J Clin Invest. 2005;  115 860-869
• 84 Sun R, Tian Z, Kulkarni S. et al . IL-6 prevents T cell-mediated hepatitis via inhibition of NKT cells in CD4⁺ T cell- and STAT3-dependent manners.  J Immunol. 2004;  172 5648-5655
• 85 Radaeva S, Sun R, Pan H. et al . 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
• 86 He Y, Chen H, Quon M J. et al . The mouse obese gene. Genomic organization, promoter activity, and activation by CCAAT/enhancer-binding protein-α.  J Biol Chem. 1995;  270 28 887-28 891
• 87 Yang S Q, Kin H Z, Lane M D. et al . Obesity increases sensitivity to endotoxin liver injury: implications fort he pathogenesis of steatohepatitis.  Proc Natl Acad Sci USA. 1997;  94 2557-2562
• 88 Siegmund B, Lear-Kaul K C, Faggioni R. et al . Leptin deficiency, not obesity, protects mice from Con A-induced hepatitis.  Eur J Immunol. 2002;  32 552-560
• 89 Diao H, Kon S, Iwabuchi K. et al . Osteopontin as a mediator of NKT cell function in T cell-mediated liver disease.  Immunity. 2004;  21 539-550
• 90 Sahai A Malladi P, Melin-Aldana H. et al . Upregulation of osteopontin expression is involved in the development of non-alcoholic steatohepatitis in a dietary murine model.  Am J Physiol Gastrointest Liver Physiol. 2004;  287 264-273
• 91 Wolf A M, Wolf D, Avila M A. et al . Up-regulation of the anti-inflammatory adipokine adiponectin in acute liver failure in mice.  J Hepatol. 2006;  44 537-543
• 92 Kremer M, Hines I N, Milton R J. et al . Favored T helper 1 response in a mouse model of hepatosteatosis is associated with enhanced T cell-mediated hepatitis.  Hepatology. 2006;  44 216-227
• 93 Van Kaer L. α-Galactosylceramide therapy for autoimmune diseases: prospects and obstracles.  Nature Rev Immunol. 2005;  5 31-42