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Z Gastroenterol 2002; 40(8): 587-600
DOI: 10.1055/s-2002-33418
Übersicht
© Karl Demeter Verlag im Georg Thieme Verlag Stuttgart · New York

Functional Relevance of Soluble TNF-α, Transmembrane TNF-α and TNF-Signal Transduction in Gastrointestinal Diseases with Special Reference to Inflammatory Bowel Diseases

Funktionelle Bedeutung von löslichem TNF, membranständigem TNF und TNF-Signaltransduktion bei gastrointestinalen Erkrankungen unter besonderer Berücksichtigung der chronisch entzündlichen DarmerkrankungenM. H. Holtmann1 , M. Schütz1 , P. R. Galle1 , M. F. Neurath1
  • 1Department of Medicine, Johannes-Gutenberg-University, Mainz
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Publication History

manuscript recieved: 11.12.2001

accepted after revision: 21.1.2002

Publication Date:
19 August 2002 (online)

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Zusammenfassung

Durch umfangreiche klinische und grundlagenwissenschaftliche Untersuchungen konnte die zentrale Rolle des Tumornekrosefaktors-α für die Pathogenese chronisch entzündlicher Erkrankungen wie der chronisch entzündlichen Darmerkrankungen nachgewiesen werden. Dieses hat zur Entwicklung viel versprechender therapeutischer Anti-TNF-Strategien geführt. Es gibt zunehmend Hinweise, dass TNF-α auch eine Schlüsselrolle bei anderen gastrointestinalen Erkrankungen spielt wie Helicobacter-pylori-Infektionen, Pankreatitis, Virushepatitis und toxischen Leberschäden. Die Wirkung von TNF-α auf zellulärer Ebene wird durch zwei Zelloberflächenrezeptoren, TNF-R1 (p60) und TNF-R2 (p80), vermittelt. Die Funktion dieser Rezeptoren und die folgenden intrazellulären Signaltransduktionswege sind eingehend in In-vitro-Systemen untersucht worden. Es ist zu erwarten, dass es besonders kritische Schritte in der TNF-Signaltransduktion gibt, die bei diesen Krankheiten fehlreguliert sind. Die Aufdeckung dieser möglichen Fehlregulationen könnte zu einem besseren Verständnis der Pathogenese dieser Krankheiten, vor allem der chronisch entzündlichen Darmerkrankungen, beitragen und möglicherweise neue, spezifischere therapeutische Ansatzpunkte liefern. Ziel dieser Arbeit ist es, eine Übersicht über den gegenwärtigen Kenntnisstand zur TNF-Signaltransduktion bei ausgewählten gastrointestinalen Erkrankungen unter besonderer Berücksichtigung der chronisch entzündlichen Darmerkrankungen zu geben. Schließlich sollen die Implikationen für zukünftige Forschungsrichtungen diskutiert werden.

Abstract

As a result of extensive clinical and basic research, the pivotal role of tumour necrosis factor (TNF) in the pathogenesis of chronic inflammatory diseases such as inflammatory bowel disease (IBD) has now generally been acknowledged. This has led to promising clinically effective anti-TNF-strategies. Of note, there is more and more evidence that TNF seems to play a key role in other gastrointestinal diseases including Helicobacter pylori infection, pancreatitis, viral hepatitis and toxic liver damage, too. The action of TNF at the cellular level is mediated by two cell surface receptors, TNF-R1 (p60) and TNF-R2 (p80). The function of these receptors and the downstream intracellular signal transduction pathway have been extensively studied in vitro and it can be expected, that there are critically important steps in TNF-signal transduction that might be dysregulated in these disease states. Their elucidation could lead to a better understanding of the pathogenesis of these diseases, in particular IBD and potentially reveal new, more specific therapeutic targets. Objective of this review is to give an overview about the current knowledge on TNF signal transduction in relationship to selected examples of important gastrointestinal disorders with special focus on IBD. Finally, the implications for future research efforts will be discussed.

Schlüsselwörter

TNF-Signaltransduktion - gastrointestinale Erkrankungen - chronisch entzündliche Darmerkrankungen

Key words

TNF-α - Signal Transduction - Gastrointestinal Disorders - Inflammatory Bowel Disease

References

  • 1 Aversa G, Punnonen J, de Vries J E. The 26-kD transmembrane form of tumor necrosis factor alpha on activated CD4+ T cell clones provides a costimulatory signal for human B cell activation.  J Exp Med. 1993;  177 (no. 6) 1575
    Search in Google Scholar
  • 2 Tang P, Hung M C, Klostergaard J. Himan pro-tumor necrosis factor is a homotrimer.  Biochemstry. 1996;  35 (no. 25) 8216
    Search in Google Scholar
  • 3 Beutler B, Van Huffel C. An evolutionary and functional approach to the TNF receptor/ligand family.  Ann N Y Acad Sci. 1994;  730 118
    Search in Google Scholar
  • 4 Spies T, Blanck G, Bresnahan M, Sands J, Strominger J L. A new cluster of genes within the human major histocompatibility complex.  Science. 1989;  243 (no. 4888) 214
    Search in Google Scholar
  • 5 Black R A, Rauch C T, Kozlosky C J. et al . A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells.  Nature. 1997;  385 (no. 6618) 729
    Search in Google Scholar
  • 6 Moss M L, Jin S L, Milla M E. et al . Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha.  Nature. 1997;  385 (no. 6618) 733
    Search in Google Scholar
  • 7 Perez C, Albert I, DeFay K. et al . A nonsecretable cell surface mutant of tumor necrosis factor (TNF) kills by cell-to-cell contact.  Cell. 1990;  63 (no. 2) 251
    Search in Google Scholar
  • 8 Eck M J, Beutler B, Kuo G, Merryweather J P, Sprang S R. Crystallization of trimeric recombinant human tumor necrosis factor (cachectin).  J Biol Chem. 198;  263 (no. 26) 12816
    Search in Google Scholar
  • 9 Han J, Thompson P, Beutler B. Dexamethasone and pentoxifylline inhibit endotoxin-induced cachectin/tumor necrosis factor synthesis at separate points in the signaling pathway.  J Exp Med. 1990;  172 (no. 1) 391
    Search in Google Scholar
  • 10 Caput D, Beutler B, Hartog K. et al . Identification of a common nucleotide sequence in the 3’-untranslated region of mRNA molecules specifying inflammatory mediators.  Proc Natl Acad Sci U S A. 1986;  83 (no. 6) 1670
    Search in Google Scholar
  • 11 Brockhaus M, Schoenfeld H J, Schlaeger E J. et al . Identification of two types of tumor necrosis factor receptors on human cell lines by monoclonal antibodies.  Proc Natl Acad Sci U S A. 1990;  87 (no. 8) 3127
    Search in Google Scholar
  • 12 Schall T J, Lewis M, Koller K J. et al . Molecular cloning and expression of a receptor for human tumor necrosis factor.  Cell. 1990;  61 (no. 2) 361
    Search in Google Scholar
  • 13 Baker E, Chen L Z, Smith C A. et al . Chromosomal location of the human tumor necrosis factor receptor genes.  Cytogenet Cell Genet. 1991;  57 (no. 2-3) 117
    Search in Google Scholar
  • 14 Fuchs P, Strehl S, Dworzak M, Himmler A, Ambros P F. Structure of the human TNF receptor 1 (p60) gene (TNFR1) and localization to chromosome 12p13 [corrected].  Genomics. 1992;  13 (no. 1) 219
    Search in Google Scholar
  • 15 Thoma B, Grell M, Pfizenmaier K, Scheurich P. Identification of a 60-kD tumor necrosis factor (TNF) receptor as the major signal transducing component in TNF responses.  J Exp Med. 1990;  172 (no. 4) 1019
    Search in Google Scholar
  • 16 Grell M, Douni E, Wajant H. et al . The transmembrane form of tumor necrosis factor is the prime activating ligand of the 80 kDa tumor necrosis factor receptor.  Cell. 1995;  83 (no. 5) 793
    Search in Google Scholar
  • 17 Weiss T, Grell M, Hessabi B. et al . Enhancement of TNF receptor p60-mediated cytotoxicity by TNF receptor p80: requirement of the TNF receptor-associated factor-2 binding site.  J Immunol. 1997;  158 (no. 5) 2398
    Search in Google Scholar
  • 18 Haas E, Grell M, Wajant H, Scheurich P. Continuous autotropic signaling by membrane-expressed tumor necrosis factor.  J Biol Chem. 1999;  274 (no. 25) 18107
    Search in Google Scholar
  • 19 Alexopoulou L, Pasparakis M, Kollias G. A murine transmembrane tumor necrosis factor (TNF) transgene induces arthritis by cooperative p55/p75 TNF receptor signaling.  Eur J Immunol. 1997;  27 (no. 10) 2588
    Search in Google Scholar
  • 20 Arch R H, Gedrich R W, Thompson C B. Tumor necrosis factor receptor-associated factors (TRAFs) - a family of adapter proteins that regulates life and death.  Genes Dev. 1998;  12 (no. 18) 2821
    Search in Google Scholar
  • 21 Chinnaiyan A M, O’Rourke K, Tewari M, Dixit V M. FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis.  Cell. 1995;  81 (no. 4) 505
    Search in Google Scholar
  • 22 Hsu H, Xiong J, Goeddel D V. The TNF receptor 1-associated protein TRADD signals cell death and NF- kappa B activation.  Cell. 1995;  81 (no. 4) 495
    Search in Google Scholar
  • 23 Hsu H, Shu H B, Pan M G, Goeddel D V. TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways.  Cell. 1996;  84 (no. 2) 299
    Search in Google Scholar
  • 24 Engelmann H, Holtmann H, Brakebusch C. et al . Antibodies to a soluble form of a tumor necrosis factor (TNF) receptor have TNF-like activity.  J Biol Chem. 1990;  265 (no. 24) 14497
    Search in Google Scholar
  • 25 Banner D W, D’Arcy A, Janes W. et al . Crystal structure of the soluble human 55 kd TNF receptor-human TNF beta complex: implications for TNF receptor activation.  Cell. 1993;  73 (no. 3) 431
    Search in Google Scholar
  • 26 Bazzoni F, Alejos E, Beutler B. Chimeric tumor necrosis factor receptors with constitutive signaling activity.  Proc Natl Acad Sci USA. 1995;  92 (no. 12) 5376
    Search in Google Scholar
  • 27 Rothe M, Wong S C, Henzel W J, Goeddel D V. A novel family of putative signal transducers associated with the cytoplasmic domain of the 75 kDa tumor necrosis factor receptor.  Cell. 1994;  78 (no. 4) 681
    Search in Google Scholar
  • 28 Takeuchi M, Rothe M, Goeddel D V. Anatomy of TRAF2. Distinct domains for nuclear factor-kappaB activation and association with tumor necrosis factor signaling proteins.  J Biol Chem. 1996;  271 (no. 33) 19935
    Search in Google Scholar
  • 29 Auphan N, DiDonato J A, Rosette C, Helmberg A, Karin M. Immunosuppression by glucocorticoids: inhibition of NF-kappa B activity through induction of I kappa B synthesis.  Science. 1995;  270 (no. 5234) 286
    Search in Google Scholar
  • 30 Neurath M F, Becker C, Barbulescu K. Role of NF-kappaB in immune and inflammatory responses in the gut.  Gut. 1998;  43 (no. 6) 856
    Search in Google Scholar
  • 31 Yin M J, Yamamoto Y, Gaynor R B. The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta.  Nature. 1998;  396 (no. 6706) 77
    Search in Google Scholar
  • 32 Wang C Y, Mayo M W, Korneluk R G, Goeddel D V, Baldwin A S Jr. NF-kappaB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c- IAP2 to suppress caspase-8 activation.  Science. 1998;  281 (no. 5383) 1680
    Search in Google Scholar
  • 33 Rothe M, Xiong J, Shu H B, Williamson K, Goddard A, Goeddel D V. I-TRAF is a novel TRAF-interacting protein that regulates TRAF-mediated signal transduction.  Proc Natl Acad Sci U S A. 1996;  93 (no. 16) 8241
    Search in Google Scholar
  • 34 Opipari A W Jr, Boguski M S, Dixit V M. The A20 cDNA induced by tumor necrosis factor alpha encodes a novel type of zinc finger protein.  J Biol Chem. 1990;  265(no. 25) 14705
    Search in Google Scholar
  • 35 Song H Y, Rothe M, Goeddel D V. The tumor necrosis factor-inducible zinc finger protein A20 interacts with TRAF1/TRAF2 and inhibits NF-kappaB activation.  Proc Natl Acad Sci U S A. 1996;  93 (no. 13) 6721
    Search in Google Scholar
  • 36 Darnay B G, Singh S, Aggarwal B B. The p80 TNF receptor-associated kinase (p80TRAK) associates with residues 354 - 397 of the p80 cytoplasmic domain: similarity to casein kinase.  FEBS Lett. 1997;  406 (no. 1-2) 101
    Search in Google Scholar
  • 37 Darnay B G, Reddy S A, Aggarwal B B. Identification of a protein kinase associated with the cytoplasmic domain of the p60 tumor necrosis factor receptor.  J Biol Chem. 1994;  269 (no. 32) 20299
    Search in Google Scholar
  • 38 Tartaglia L A, Ayres T M, Wong G H, Goeddel D V. A novel domain within the 55 kd TNF receptor signals cell death.  Cell. 1993;  74 (no. 5) 845
    Search in Google Scholar
  • 39 Boldin M P, Varfolomeev E E, Pancer Z. et al . A novel protein that interacts with the death domain of Fas/APO1 contains a sequence motif related to the death domain.  J Biol Chem. 1995;  270 (no. 14) 7795
    Search in Google Scholar
  • 40 Stanger B Z, Leder P, Lee T H, Kim E, Seed B. RIP: a novel protein containing a death domain that interacts with Fas/APO-1 (CD95) in yeast and causes cell death.  Cell. 1995;  81 (no. 4) 513
    Search in Google Scholar
  • 41 Hsu H, Huang J, Shu H B, Baichwal V, Goeddel D V. TNF-dependent recruitment of the protein kinase RIP to the TNF receptor- 1 signaling complex.  Immunity. 1996;  4 (no. 4) 387
    Search in Google Scholar
  • 42 Yeh W C, Pompa J L, McCurrach M E. et al . FADD: essential for embryo development and signaling from some, but not all, inducers of apoptosis.  Science. 1998;  279 (no. 5358) 1954
    Search in Google Scholar
  • 43 Muzio M, Chinnaiyan A M, Kischkel F C. et al . FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex.  Cell. 1996;  85 (no. 6) 817
    Search in Google Scholar
  • 44 Rothe M, Sarma V, Dixit V M, Goeddel D V. TRAF2-mediated activation of NF-kappa B by TNF receptor 2 and CD40.  Science. 1995;  269 (no. 5229) 1424
    Search in Google Scholar
  • 45 Lee S Y, Kaufman D R, Mora A L. et al . Stimulus-dependent synergism of the antiapoptotic tumor necrosis factor receptor-associated factor 2 (TRAF2) and nuclear factor kappaB pathways.  J Exp Med. 1998;  188 (no. 7) 1381
    Search in Google Scholar
  • 46 Yeh W C, Shahinian A, Speiser D. et al . Early lethality, functional NF-kappaB activation, and increased sensitivity to TNF-induced cell death in TRAF2-deficient mice.  Immunity. 1997;  7 (no. 5) 715
    Search in Google Scholar
  • 47 Schutze S, Berkovic D, Tomsing O, Unger C, Kronke M. Tumor necrosis factor induces rapid production of 1’2’diacylglycerol by a phosphatidylcholine-specific phospholipase C.  J Exp Med. 1991;  174 (no. 5) 975
    Search in Google Scholar
  • 48 Liu J, Mathias S, Yang Z, Kolesnick R N. Renaturation and tumor necrosis factor-alpha stimulation of a 97-kDa ceramide-activated protein kinase.  J Biol Chem. 1994;  269 (no. 4) 3047
    Search in Google Scholar
  • 49 Blenis J. Signal transduction via the MAP kinases: proceed at your own RSK.  Proc Natl Acad Sci U S A. 1993;  90 (no. 13) 5889
    Search in Google Scholar
  • 50 Beutler B. Tumor necrosis factors: the molecules and their emerging role in medicine. New York; Raven Press 1992
    Search in Google Scholar
  • 51 Tracey K J, Cerami A. Tumor necrosis factor: a pleiotropic cytokine and therapeutic target.  Annu Rev Med. 1994;  45 (no. 9) 491
    Search in Google Scholar
  • 52 Carswell E A, Old L J, Kassel R L. et al . An endotoxin-induced serum factor that causes necrosis of tumors.  Proc Natl Acad Sci U S A. 1975;  72 3666
    Search in Google Scholar
  • 53 Rothe J, Lesslauer W, Lotscher H. et al . Mice lacking the tumour necrosis factor receptor 1 are resistant to TNF- mediated toxicity but highly susceptible to infection by Listeria monocytogenes.  Nature. 1993;  364 (no. 6440) 798
    Search in Google Scholar
  • 54 Marino M W, Dunn A, Grail D. et al . Characterization of tumor necrosis factor-deficient mice.  Proc Natl Acad Sci USA. 1997;  94 (no. 15) 8093
    Search in Google Scholar
  • 55 Tracey K J, Cerami A. Tumor necrosis factor, other cytokines and disease.  Annu Rev Cell Biol. 1993;  9 (no. 4) 317
    Search in Google Scholar
  • 56 Pasparakis M, Alexopoulou L, Episkopou V, Kollias G. Immune and inflammatory responses in TNF alpha-deficient mice: a critical requirement for TNF alpha in the formation of primary B cell follicles, follicular dendritic cell networks and germinal centers, and in the maturation of the humoral immune response.  J Exp Med. 1996;  184 1397
    Search in Google Scholar
  • 57 Gamble J R, Harlan J M, Klebanoff S J, Vadas M A. Stimulation of the adherence of neutrophils to umbilical vein endothelium by human recombinant tumor necrosis factor.  Proc Natl Acad Sci USA. 1985;  82 (no. 24) 8667
    Search in Google Scholar
  • 58 Carlos T M, Harlan J M. Leukocyte-endothelial adhesion molecules.  Blood. 1994;  84 (no. 7) 2068
    Search in Google Scholar
  • 59 Kuijpers T W, Hakkert B C, Hart M H, Roos D. Neutrophil migration across monolayers of cytokine-prestimulated endothelial cells: a role for platelet-activating factor and IL-8.  J Cell Biol. 1992;  117 (no. 3) 565
    Search in Google Scholar
  • 60 Paleolog E M, Delasalle S A, Buurman W A, Feldmann M. Functional activities of receptors for tumor necrosis factor-alpha on human vascular endothelial cells.  Blood. 1994;  84 (no. 8) 2578
    Search in Google Scholar
  • 61 Levi M, ten C ate H, van der Poll T, van Deventer S J. Pathogenesis of disseminated intravascular coagulation in sepsis.  Jama. 1993;  270 (no. 8) 975
    Search in Google Scholar
  • 62 van der Poll T, Levi M, Buller H R. et al . Fibrinolytic response to tumor necrosis factor in healthy subjects.  J Exp Med. 1991;  174 (no. 3) 729
    Search in Google Scholar
  • 63 van der Poll T, Jansen J, van Leenen D. et al . Release of soluble receptors for tumor necrosis factor in clinical sepsis and experimental endotoxemia.  J Infect Dis. 1993;  168 (no. 4) 955
    Search in Google Scholar
  • 64 Tracey K J. Tumor necrosis factor (cachectin) in the biology of septic shock syndrome.  Circ Shock. 1991;  35 (no. 2) 123
    Search in Google Scholar
  • 65 Tracey K J, Fong Y, Hesse D G. et al . Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia.  Nature. 19987;  330 (no. 6149) (no. 3) 662
    Search in Google Scholar
  • 66 Abraham E, Anzueto A, Gutierrez G. et al . Double-blind randomised controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock. NORASEPT II Study Group.  Lancet. 1998;  351 (no. 9107) 929
    Search in Google Scholar
  • 67 Asher A, Mule J J, Reichert C M, Shiloni E, Rosenberg S A. Studies on the anti-tumor efficacy of systemically administered recombinant tumor necrosis factor against several murine tumors in vivo.  J Immunol. 1987;  138 963
    Search in Google Scholar
  • 68 Lejeune F, Bauer J, Leyvraz S, Lienard D. Disseminated melanoma, preclinical therapeutic studies, clinical trials, and patient treatment.  Curr Opin Oncol. 1993;  5 (no. 2) 390
    Search in Google Scholar
  • 69 Clauss M, Ryan J, Stern D. Modulation of endothelial cell hemostatic properties by TNF: Insight into the role endothelium in the host response to inflammatory stimuli. Beutler B Tumor Necrosis Factors: The Molecules and Their Emerging Role in Medicine New York; Raven Press 1992: 49 pp.
    Search in Google Scholar
  • 70 Nawroth P, Handley D, Matsueda G. et al . Tumor necrosis factor/ cachectin-induced intravascular fibrin formation in meth A fibrosarcomas.  J Exp Med. 1988;  168 (no. 2) 637
    Search in Google Scholar
  • 71 Urban J L, Shepard H M, Rothstein J L, Sugarman B J, Schreiber H. Tumor necrosis factor: a potent effector molecule for tumor cell killing by activated macrophages.  Proc Natl Acad Sci U S A. 1986;  83 (no. 14) 5233
    Search in Google Scholar
  • 72 Keffer J, Probert L, Cazlaris H. et al . Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis.  Embo J. 1991;  10 (no. 13) (no. 8930) 4025
    Search in Google Scholar
  • 73 Elliott M J, Maini R N, Feldmann M. et al . Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis.  Lancet. 1994;  344 1105
    Search in Google Scholar
  • 74 Moreland L W, Baumgartner S W, Schiff M H. et al . Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein.  N Engl J Med. 1997;  337 (no. 3) 141
    Search in Google Scholar
  • 75 Le Hir M, Bluethmann H, Kosco-Vilbois M H. et al . Tumor necrosis factor receptor-1 signaling is required for differentiation of follicular dendritic cells, germinal center formation, and full antibody responses.  J Inflamm. 1995;  47 (no. 1 - 2) (no. 4) 76
    Search in Google Scholar
  • 76 Pfeffer K, Matsuyama T, Kundig T M. et al . Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection.  Cell. 1993;  73 (no. 3) 457
    Search in Google Scholar
  • 77 Neumann B, Machleidt T, Lifka A. et al . Crucial role of 55-kilodalton TNF receptor in TNF-induced adhesion molecule expression and leukocyte organ infiltration.  J Immunol. 1996;  156 1587
    Search in Google Scholar
  • 78 Erickson S L, de Sauvage F J, Kikly K. et al . Decreased sensitivity to tumour-necrosis factor but normal T-cell development in TNF receptor-2-deficient mice.  Nature. 1994;  372 (no. 6506) 560
    Search in Google Scholar
  • 79 Lucas R, Juillard P, Decoster E. et al . Crucial role of tumor necrosis factor (TNF) receptor 2 and membrane- bound TNF in experimental cerebral malaria.  Eur J Immunol. 1997;  27 (no. 7) 1719
    Search in Google Scholar
  • 80 Douni E, Kollias G. A critical role of the p75 tumor necrosis factor receptor (p75TNF-R) in organ inflammation independent of TNF, lymphotoxin alpha, or the p55TNF- R.  J Exp Med. 1998;  188 (no. 7) 1343
    Search in Google Scholar
  • 81 Schroder J, Stuber F, Gallati H, Schade F U, Kremer B. Pattern of soluble TNF receptors I and II in sepsis.  Infection. 1995;  23 (no. 3) 143
    Search in Google Scholar
  • 82 Marinos G, Naoumov N V, Rossol S. et al . Tumor necrosis factor receptors in patients with chronic hepatitis B virus infection.  Gastroenterology. 1995;  108 (no. 5) 1453
    Search in Google Scholar
  • 83 de Beaux A C, Ross J A, Maingay J P, Fearon K C, Carter D C. Proinflammatory cytokine release by peripheral blood mononuclear cells from patients with acute pancreatitis.  Br J Surg. 1996;  83 (no. 8) 1071
    Search in Google Scholar
  • 84 Gabay C, Cakir N, Moral F. et al . Circulating levels of tumor necrosis factor soluble receptors in systemic lupus erythematosus are significantly higher than in other rheumatic diseases and correlate with disease activity.  J Rheumatol. 1997;  24 (no. 2) 303
    Search in Google Scholar
  • 85 Godfried M H, van der Poll T, Jansen J. et al . Soluble receptors for tumour necrosis factor: a putative marker of disease progression in HIV infection.  Aids. 1993;  7 (no. 1) 33
    Search in Google Scholar
  • 86 Kusters S, Tiegs G, Alexopoulou L. et al . In vivo evidence for a functional role of both tumor necrosis factor (TNF) receptors and transmembrane TNF in experimental hepatitis.  Eur J Immunol. 1997;  27 (no. 11) 2870
    Search in Google Scholar
  • 87 Moss S F, Legon S, Davies J, Calam J. Cytokine gene expression in Helicobacter pylori associated antral gastritis.  Gut. 1994;  35 (no. 11) 1567
    Search in Google Scholar
  • 88 Crabtree J E, Shallcross Z M, Heatley R V, Wyatt J I. Mucosal tumour necrosis factor alpha and interleukin-6 in patients with Helicobacter pylori associated gastritis.  Gut. 1991;  32 (no. 12) 1473
    Search in Google Scholar
  • 89 Ishihara S, Fukuda R, Fukumoto S. Cytokine gene expression in the gastric mucosa: its role in chronic gastritis.  J Gastroenterol. 1996;  31 (no. 4) 485
    Search in Google Scholar
  • 90 Houghton J, Macera-Bloch L S, Harrison L, Kim K H, Korah R M. Tumor necrosis factor alpha and interleukin 1beta up-regulate gastric mucosal Fas antigen expression in Helicobacter pylori infection.  Infect Immun. 2000;  68 (no. 3) 1189
    Search in Google Scholar
  • 91 Rudi J, Kuck D, Strand S. et al . Involvement of the CD95 (APO-1/Fas) receptor and ligand system in Helicobacter pylori-induced gastric epithelial apoptosis.  J Clin Invest. 1998;  102 (no. 8) 1506
    Search in Google Scholar
  • 92 Santucci L, Fiorucci S, Giansanti M. et al . Pentoxifylline prevents indomethacin induced acute gastric mucosal damage in rats: role of tumour necrosis factor alpha.  Gut. 1994;  35 (no. 7) 909
    Search in Google Scholar
  • 93 Hermann G E, Tovar C A, Rogers R C. Induction of endogenous tumor necrosis factor-alpha: suppression of centrally stimulated gastric motility.  Am J Physiol. 1999;  276 (no. 1 Pt 2) R59
    Search in Google Scholar
  • 94 Kiyama T, Onda M, Tokunaga A. et al . The presence of tumor necrosis factor-alpha and its antibody in the sera of cachexic patients with gastrointestinal cancer.  Surg Today. 1994;  24 (no. 8) 759
    Search in Google Scholar
  • 95 Ohno M, Kato M, Nakamura T, Saitoh Y. Gene expression for tumor necrosis factor alpha and its production in gastric cancer patients.  Jpn J Cancer Res. 1994;  85 (no. 10) 1029
    Search in Google Scholar
  • 96 Beutler B, van Huffel C. Unraveling function in the TNF ligand and receptor families.  Science. 1994;  264 (no. 5159) 667
    Search in Google Scholar
  • 97 Norman J G, Fink G W, Denham W. et al . Tissue-specific cytokine production during experimental acute pancreatitis. A probable mechanism for distant organ dysfunction.  Dig Dis Sci. 1997;  42 (no. 8) (no. 5) 1783
    Search in Google Scholar
  • 98 Blanchard 2nd J A, Barve S, Joshi-Barve S, Talwalker R, Gates Jr L K. Cytokine production by CAPAN-1 and CAPAN-2 cell lines.  Dig Dis Sci. 2000;  45 927
    Search in Google Scholar
  • 99 Gukovskaya A S, Gukovsky I, Zaninovic V. et al . Pancreatic acinar cells produce, release, and respond to tumor necrosis factor-alpha. Role in regulating cell death and pancreatitis.  J Clin Invest. 1997;  100 (no. 7) (no. 1) 1853
    Search in Google Scholar
  • 100 Lundberg A H, Eubanks 3rd J W, Henry J. et al . Trypsin stimulates production of cytokines from peritoneal macrophages in vitro and in vivo.  Pancreas. 2000;  21 41
    Search in Google Scholar
  • 101 Steinle A U, Weidenbach H, Wagner M, Adler G, Schmid R M. NF-kappaB/Rel activation in cerulein pancreatitis.  Gastroenterology. 1999;  116 (no. 2) 420
    Search in Google Scholar
  • 102 Ishizuka N, Yagui K, Tokuyama Y. et al . Tumor necrosis factor alpha signaling pathway and apoptosis in pancreatic beta cells.  Metabolism. 1999;  48 (no. 12) 1485
    Search in Google Scholar
  • 103 Stephens L A, Thomas H E, Ming L. et al . Tumor necrosis factor-alpha-activated cell death pathways in NIT-1 insulinoma cells and primary pancreatic beta cells.  Endocrinology. 1999;  140 (no. 7) 3219
    Search in Google Scholar
  • 104 Sheron N, Lau J, Daniels H. et al . Increased production of tumour necrosis factor alpha in chronic hepatitis B virus infection.  J Hepatol. 1991;  12 (no. 2) 241
    Search in Google Scholar
  • 105 Larrea E, Garcia N, Qian C, Civeira M P, Prieto J. Tumor necrosis factor alpha gene expression and the response to interferon in chronic hepatitis C.  Hepatology. 1996;  23 (no. 2) 210
    Search in Google Scholar
  • 106 Kallinowski B, Haseroth K, Marinos G. et al . Induction of tumour necrosis factor (TNF) receptor type p55 and p75 in patients with chronic hepatitis C virus (HCV) infection.  Clin Exp Immunol. 1998;  111 (no. 2) 269
    Search in Google Scholar
  • 107 Gonzalez-Amaro R, Garcia-Monzon C, Garcia-Buey L. et al . Induction of tumor necrosis factor alpha production by human hepatocytes in chronic viral hepatitis.  J Exp Med. 1994;  179 (no. 3) 841
    Search in Google Scholar
  • 108 Ruby J, Bluethmann H, Peschon J J. Antiviral activity of tumor necrosis factor (TNF) is mediated via p55 and p75 TNF receptors.  J Exp Med. 1997;  186 (no. 9) 1591
    Search in Google Scholar
  • 109 Zhu N, Khoshnan A, Schneider R. et al . Hepatitis C virus core protein binds to the cytoplasmic domain of tumor necrosis factor (TNF) receptor 1 and enhances TNF-induced apoptosis.  J Virol. 1998;  72 (no. 5) 3691
    Search in Google Scholar
  • 110 Marusawa H, Hijikata M, Chiba T, Shimotohno K. Hepatitis C virus core protein inhibits Fas- and tumor necrosis factor alpha-mediated apoptosis via NF-kappaB activation.  J Virol. 1999;  73 (no. 6) 4713
    Search in Google Scholar
  • 111 Marusawa H, Hijikata M, Watashi K, Chiba T, Shimotohno K. Regulation of Fas-mediated apoptosis by NF-kappaB activity in human hepatocyte derived cell lines.  Microbiol Immunol. 2001;  45 (no. 6) 483
    Search in Google Scholar
  • 112 Tai D I, Tsai S L, Chen Y M. et al . Activation of nuclear factor kappaB in hepatitis C virus infection: implications for pathogenesis and hepatocarcinogenesis.  Hepatology. 2000;  31 (no. 3) 656
    Search in Google Scholar
  • 113 Bernal W, Moloney M, Underhill J, Donaldson P T. Association of tumor necrosis factor polymorphism with primary sclerosing cholangitis.  J Hepatol. 1999;  30 (no. 2) 237
    Search in Google Scholar
  • 114 Cookson S, Constantini P K, Clare M. et al . Frequency and nature of cytokine gene polymorphisms in type 1 autoimmune hepatitis.  Hepatology. 1999;  30 (no. 4) 851
    Search in Google Scholar
  • 115 Czaja A J, Cookson S, Constantini P K. et al . Cytokine polymorphisms associated with clinical features and treatment outcome in type 1 autoimmune hepatitis.  Gastroenterology. 1999;  117 (no. 3) 645
    Search in Google Scholar
  • 116 Gordon M A, Oppenheim E, Camp N J. et al . Primary biliary cirrhosis shows association with genetic polymorphism of tumour necrosis factor alpha promoter region.  J Hepatol. 1999;  31 (no. 2) 242
    Search in Google Scholar
  • 117 Grove J, Daly A K, Bassendine M F, Day C P. Association of a tumor necrosis factor promoter polymorphism with susceptibility to alcoholic steatohepatitis.  Hepatology. 1997;  26 (no. 1) 143
    Search in Google Scholar
  • 118 Spengler U, Moller A, Jung M C. et al . T lymphocytes from patients with primary biliary cirrhosis produce reduced amounts of lymphotoxin, tumor necrosis factor and interferon-gamma upon mitogen stimulation.  J Hepatol. 1992;  15 (no. 1 - 2) 129
    Search in Google Scholar
  • 119 Naveau S, Emilie D, Balian A. et al . Plasma levels of soluble tumor necrosis factor receptors p55 and p75 in patients with alcoholic liver disease of increasing severity.  J Hepatol. 1998;  28 (no. 5) 778
    Search in Google Scholar
  • 120 Iimuro Y, Gallucci R M, Luster M I, Kono H, Thurman R G. Antibodies to tumor necrosis factor alfa attenuate hepatic necrosis and inflammation caused by chronic exposure to ethanol in the rat.  Hepatology. 1997;  26 (no. 6) 1530
    Search in Google Scholar
  • 121 Hadziselimovic F, Emmons L R, Gallati H. Soluble tumour necrosis factor receptors p55 and p75 in the urine monitor disease activity and the efficacy of treatment of inflammatory bowel disease.  Gut. 1995;  37 (no. 2) 260
    Search in Google Scholar
  • 122 Braegger C P, Nicholls S, Murch S H, Stephens S, MacDonald T T. Tumour necrosis factor alpha in stool as a marker of intestinal inflammation.  Lancet. 1992;  339 (no. 8785) 89
    Search in Google Scholar
  • 123 Murch S H, Braegger C P, Walker-Smith J A, MacDonald T T. Location of tumour necrosis factor alpha by immunohistochemistry in chronic inflammatory bowel disease.  Gut. 1993;  34 (no. 12) 1705
    Search in Google Scholar
  • 124 Reinecker H C, Steffen M, Witthoeft T. et al . Enhanced secretion of tumour necrosis factor-alpha, IL-6, and IL-1 beta by isolated lamina propria mononuclear cells from patients with ulcerative colitis and Crohn’s disease.  Clin Exp Immunol. 1993;  94 (no. 1) 174
    Search in Google Scholar
  • 125 Reimund J M, Wittersheim C, Dumont S. et al . Mucosal inflammatory cytokine production by intestinal biopsies in patients with ulcerative colitis and Crohn’s disease.  J Clin Immunol. 1996;  16 (no. 3) 144
    Search in Google Scholar
  • 126 Plevy S E, Landers C J, Prehn J. et al . A role for TNF-alpha and mucosal T helper-1 cytokines in the pathogenesis of Crohn’s disease.  J Immunol. 1997;  159 (no. 12) 6276
    Search in Google Scholar
  • 127 Pender S L, Breese E J, Gunther U. et al . Suppression of T cell-mediated injury in human gut by interleukin 10: role of matrix metalloproteinases.  Gastroenterology. 1998;  115 (no. 3) 573
    Search in Google Scholar
  • 128 Monteleone G, Biancone L, Marasco R. et al . Interleukin 12 is expressed and actively released by Crohn’s disease intestinal lamina propria mononuclear cells.  Gastroenterology. 1997;  112 (no. 4) 1169
    Search in Google Scholar
  • 129 Monteleone G, MacDonald T T, Wathen N C, Pallone F, Pender S L. Enhancing Lamina propria Th1 cell responses with interleukin 12 produces severe tissue injury.  Gastroenterology. 1999;  117 (no. 5) 1069
    Search in Google Scholar
  • 130 Elson C O, Sartor R B, Tennyson G S, Riddell R H. Experimental models of inflammatory bowel disease.  Gastroenterology. 1995;  109 (no. 4) 1344
    Search in Google Scholar
  • 131 Neurath M F, Fuss I, Pasparakis M. et al . Predominant pathogenic role of tumor necrosis factor in experimental colitis in mice.  Eur J Immunol. 1997;  27 (no. 7) 1743
    Search in Google Scholar
  • 132 Okayasu I, Hatakeyama S, Yamada M. et al . A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice.  Gastroenterology. 1990;  98 (no. 3) 694
    Search in Google Scholar
  • 133 Kuhn R, Lohler J, Rennick D, Rajewsky K, Muller W. Interleukin-10-deficient mice develop chronic enterocolitis.  Cell. 1993;  75 (no. 2) 263
    Search in Google Scholar
  • 134 Powrie F, Leach M W, Mauze S, Caddle L B, Coffman R L. Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C. B-17 scid mice.  Int Immunol. 1993;  5 (no. 11) (no. 5) 1461
    Search in Google Scholar
  • 135 Atreya R, Mudter J, Finotto S. et al . Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in crohn disease and experimental colitis in vivo.  Nat Med. 2000;  6 583
    Search in Google Scholar
  • 137 Corazza N, Eichenberger S, Eugster H P, Mueller C. Nonlymphocyte-derived tumor necrosis factor is required for induction of colitis in recombination activating gene (RAG)2(-/-) mice upon transfer of CD4(+)CD45RB(hi) T cells.  J Exp Med. 1999;  190 (no. 10) 1479
    Search in Google Scholar
  • 136 Kojouharoff G, Hans W, Obermeier F. et al . Neutralization of tumour necrosis factor (TNF) but not of IL-1 reduces inflammation in chronic dextran sulphate sodium-induced colitis in mice.  Clin Exp Immunol. 1997;  107 (no. 2) 353
    Search in Google Scholar
  • 138 Kontoyiannis D, Pasparakis M, Pizarro T T, Cominelli F, Kollias G. Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU- rich elements: implications for joint and gut-associated immunopathologies.  Immunity. 1999;  10 (no. 3) 387
    Search in Google Scholar
  • 139 Schreiber S, Heinig T, Thiele H G, Raedler A. Immunoregulatory role of interleukin 10 in patients with inflammatory bowel disease.  Gastroenterology. 1995;  108 (no. 5) 1434
    Search in Google Scholar
  • 140 Sands B E, Bank S, Sninsky C A. et al . Preliminary evaluation of safety and activity of recombinant human interleukin 11 in patients with active Crohn’s disease.  Gastroenterology. 1999;  117 (no. 1) 58
    Search in Google Scholar
  • 141 Sumer N, Palabiyikoglu M. Induction of remission by interferon-alpha in patients with chronic active ulcerative colitis.  Eur J Gastroenterol Hepatol. 1995;  7 (no. 7) 597
    Search in Google Scholar
  • 142 Stack W A, Mann S D, Roy A J. et al . Randomised controlled trial of CDP571 antibody to tumour necrosis factor-alpha in Crohn’s disease.  Lancet. 1997;  349 521
    Search in Google Scholar
  • 143 Evans R C, Clarke L, Heath P. et al . Treatment of ulcerative colitis with an engineered human anti-TNFalpha antibody CDP571.  Aliment Pharmacol Ther. 1997;  11 (no. 6) 1031
    Search in Google Scholar
  • 144 Knight D M, Trinh H, Le J. et al . Construction and initial characterization of a mouse-human chimeric anti-TNF antibody.  Mol Immunol. 1993;  30 (no. 16) 1443
    Search in Google Scholar
  • 145 Scallon B J, Moore M A, Trinh H, Knight D M, Ghrayeb J. Chimeric anti-TNF-alpha monoclonal antibody cA2 binds recombinant transmembrane TNF-alpha and activates immune effector functions.  Cytokine. 1995;  7 (no. 3) 251
    Search in Google Scholar
  • 146 Siegel S A, Shealy D J, Nakada M T. et al . The mouse/human chimeric monoclonal antibody cA2 neutralizes TNF in vitro and protects transgenic mice from cachexia and TNF lethality in vivo.  Cytokine. 1995;  7 (no. 1) 15
    Search in Google Scholar
  • 147 Lugering A, Schmidt M, Lugering N. et al . Infliximab induces apoptosis in monocytes from patients with chronic active crohn’s disease by using a caspase-dependent pathway.  Gastroenterology. 2001;  121 (no. 5) 1145
    Search in Google Scholar
  • 148 van Dullemen H M, van Deventer S J, Hommes D W. et al . Treatment of Crohn’s disease with anti-tumor necrosis factor chimeric monoclonal antibody (cA2).  Gastroenterology. 1995;  109 (no. 1) 129
    Search in Google Scholar
  • 149 Targan S R, Hanauer S B, van Deventer S J. et al . A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease. Crohn’s Disease cA2 Study Group.  N Engl J Med. 1997;  337 (no. 15) (no. 18) 1029
    Search in Google Scholar
  • 150 Present D H, Rutgeerts P, Targan S. et al . Infliximab for the treatment of fistulas in patients with Crohn’s disease.  N Engl J Med. 1999;  340 1398
    Search in Google Scholar
  • 151 Schreiber S. et al .ACCENT I - Study (A Crohn’s Disease Clinical rial Evaluating Infliximab in a New Long Term Treatment Regimen). Presented at the United European Gastroenterology Week Amsterdam; Oct 6-10, 2001
    Search in Google Scholar
  • 152 Bickston S J, Lichtenstein G R, Arseneau K O, Cohen R B, Cominelli F. The relationship between infliximab treatment and lymphoma in Crohn’s disease.  Gastroenterology. 1999;  117 (no. 6) 1433
    Search in Google Scholar
  • 153 Sandborn W J, Hanauer S B. Antitumor necrosis factor therapy for inflammatory bowel disease: a review of agents, pharmacology, clinical results, and safety.  Inflamm Bowel Dis. 1999;  5 (no. 2) 119
    Search in Google Scholar
  • 154 Etanercept. Soluble tumor necrosis factor receptor, TNF receptor fusion protein, TNFR-Fc, TNF 001, Enbrel.  Drugs R & D. 1999;  1 (no. 5)
    Search in Google Scholar
  • 155 Sandborn W J, Hanauer S B, Katz S. et al . Etanercept for active crohn’s disease: a randomized, double-blind, placebo-controlled trial.  Gastroenterology. 2001;  121 1088
    Search in Google Scholar
  • 156 van Denventer S JH. Transmembrane TNF-alpha, Induction of Apoptosis, and the Efficacy of TNF-Targeting Therapies in Crohn’s Disease.  Gastroenterology. 2001;  121 (no. 4) 1239-1242
    Search in Google Scholar
  • 157 Holtmann M H, Douni E, Schütz M. et al . Tumor necrosis factor-receptor 2 is upregulated on lamina propria mononuclear cells in Crohn’s disease and promotes experimental colitis in vivo.  submitted.
  • 158 Reimund J M, Dumont S, Muller C D, Kenney J S. et al . In vitro effects of oxpentifylline on inflammatory cytokine release in patients with inflammatory bowel disease.  Gut. 1997;  40 475
    Search in Google Scholar
  • 159 Bauditz J, Haemling J, Ortner M. et al . Treatment with tumour necrosis factor inhibitor oxpentifylline does not improve corticosteroid dependent chronic active Crohn’s disease.  Gut. 1997;  40 (no. 4) 470
    Search in Google Scholar
  • 160 Siegmund B, Rieder F, Albrich S. et al . Adenosine kinase inhibitor GP515 improves experimental colitis in mice.  J Pharmacol Exp Ther. 2001;  296 (no. 1) 99
    Search in Google Scholar
  • 161 Hartmann G, Bidlingmaier C, Siegmund B. et al . Specific type IV phosphodiesterase inhibitor rolipram mitigates experimental colitis in mice.  J Pharmacol Exp Ther. 2000;  292 (no. 1) 22
    Search in Google Scholar
  • 162 Meierhofer C, Dunzendorfer S, Wiedermann C J. Protein kinase C-dependent effects on leukocyte migration of thalidomide.  J Infect Dis. 1999;  180 (no. 1) 216
    Search in Google Scholar
  • 163 D’Amato R J, Loughnan M S, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis.  Proc Natl Acad Sci U S A. 1994;  91 (no. 9) 4082
    Search in Google Scholar
  • 164 Moreira A L, Sampaio E P, Zmuidzinas A. et al . Thalidomide exerts its inhibitory action on tumor necrosis factor alpha by enhancing mRNA degradation.  J Exp Med. 1993;  177 (no. 6) 1675
    Search in Google Scholar
  • 165 Ehrenpreis E D, Kane S V, Cohen L B, Cohen R D, Hanauer S B. Thalidomide therapy for patients with refractory Crohn’s disease: an open-label trial.  Gastroenterology. 1999;  117 (no. 6) 1271
    Search in Google Scholar
  • 166 Vasiliauskas E A, Kam L Y, Abreu-Martin M T. et al . An open-label pilot study of low-dose thalidomide in chronically active, steroid-dependent Crohn’s disease.  Gastroenterology. 1999;  117 (no. 6) 1278
    Search in Google Scholar
  • 167 Williams L M, Gibbons D L, Gearing A. et al . Paradoxical effects of a synthetic metalloproteinase inhibitor that blocks both p55 and p75 TNF receptor shedding and TNF alpha processing in RA synovial membrane cell cultures.  J Clin Invest. 1996;  97 (no. 12) 2833
    Search in Google Scholar

Martin H. Holtmann M.D.

Department of Medicine, Johannes-Gutenberg-University

Langenbeckstraße 1

55131 Mainz

Email: mholtman@mail.uni-mainz.de