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

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

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Martin H. Holtmann M.D.

Department of Medicine, Johannes-Gutenberg-University

Langenbeckstraße 1

55131 Mainz

Email: mholtman@mail.uni-mainz.de