TGF-β/Smad Signaling in the Injured Liver

Zusammenfassung

Direkte und indirekte Wirkmechanismen des Wachstumsfaktors TGF-β stehen im Zentrum fibrotischer Umbauprozesse in der geschädigten Leber. TGF-β aktiviert hepatische Sternzellen (HSCs), die daraufhin zu matrixsynthetisierenden Myofibroblasten transdifferenzieren. Gleichzeitig induziert TGF-β Apoptose und trägt damit zum Untergang des Leberparenchyms bei. Weiter ist TGF-β wichtig für die Wachstumskontrolle proliferierender Hepatozyten während regenerativer Prozesse. Das bedeutet, dass der gesamte durch TGF-β regulierte Wundheilungsprozess in der geschädigten Leber aus einem komplexen Netzwerk intrazellulärer und interzellulärer Interaktionen der verschiedenen Leberzelltypen resultiert. In der hier vorliegenden Übersicht wird der aktuelle Wissensstand der TGF-β-Signaltransduktion in hepatischen Sternzellen mit besonderem Augenmerk auf die Smad-vermittelten Signalwege dargestellt. Darüber hinaus wird das molekulare Zusammenspiel zwischen profibrogenen TGF-β-Effekten und antifibrogenen, durch IFN-γ ausgelösten Wegen beschrieben. Schließlich wird die Plastizität von Hepatozyten und deren epithelial-mesenchymale Transdifferenzierung im Rahmen der Fibrogenese und Hepatokarzinogenese diskutiert, wobei auch hier insbesondere die Rolle des TGF-β zentralisiert wird.

Abstract

TGF-β, acting both directly and indirectly, represents a central mediator of fibrogenic remodeling processes in the liver. Besides hepatic stellate cells (HSCs), which are induced by TGF-β to transdifferentiate to myofibroblasts and to produce extracellular matrix, hepatocytes are also strongly responsive for this cytokine, which induces apoptosis during fibrogenesis and provides growth control in regeneration processes. Based on this, TGF-β-mediated hepatic responses to injury are the result of a complex interplay between the different liver cell types. In this review we summarize the knowledge about TGF-β signal transduction in HSCs with special impact on Smad pathways. We further describe a molecular cross-talk between profibrogenic TGF-β and antifibrogenic IFN-γ signaling in liver cells. Finally, we introduce hepatocyte plasticity and epithelial-to-mesenchymal transition in the liver, which is well established in tumorigenesis, as a potential feature of fibrogenesis and highlight possible action points of TGF-β in these contexts.

TGF-β - Smad - Leber - Fibrose - HSC - EMT - Interferon-γ

TGF-β - Smad - liver - fibrosis - HSC - EMT - interferon-γ

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