Pathogenese der Leberfibrose: Regulation von hepatischen Sternzellen durch Chemokine

Zusammenfassung

Die Leberfibrose ist die gemeinsame Endstrecke chronischer Lebererkrankungen und für einen großen Teil der Mortalität und Morbidität der Erkrankungen verantwortlich. In den letzten Jahren zeigte sich, dass Chemokine und ihre Rezeptoren eine Rolle in der Entwicklung einer Leberfibrose spielen. Hierbei handelt es sich um eine Familie chemotaktischer und immunmodulierender Moleküle, die über G-Protein gekoppelte Rezeptoren auf Zielzellen wirken. Neben der klassischen Funktion einer Immunzellrekrutierung in die Leber konnten auch direkte Effekte der Chemokine auf hepatische Sternzellen nachgewiesen werden. Bisher sind 9 der 19 bekannten Chemokinrezeptoren auf hepatischen Sternzellen charakterisiert worden. Ihre Stimulation mit spezifischen Liganden führt zumeist zu einer Migration und Proliferation dieser Zellen, was überwiegend für profibrotische Effekte von Chemokinen spricht. Bisher wurden nur für den Chemokinrezeptor CXCR3 auch antifibrotische Eigenschaften auf hepatischen Sternzellen beschrieben. Hepatische Sternzellen sind jedoch nicht nur das Ziel von Chemokinen, sondern sie sind auch zur Sekretion diverser Chemokine in der Lage. Hierdurch wird u. a. die Interaktion der Zellen mit infiltrierenden Immunzellen in der Leber vermittelt. Die weitere Aufklärung dieser Interaktionen kann auf lange Sicht neue Interventionsmöglichkeiten zur Therapie fibrosierender Lebererkrankungen eröffnen. Hierzu scheinen Chemokine besonders geeignet, da bereits erste orale Chemokinrezeptorantagonisten zugelassen wurden.

Abstract

Liver fibrosis is the common sequel of chronic liver diseases and is associated with high morbidity and mortality in affected patients. In recent years, the contribution of chemokines and their receptors to liver fibrosis has been delineated. Chemokines are a family of chemotactic and immunomodulatory molecules that act through different G-protein coupled receptors on target cells. Apart from their classical function of regulating immune cell recruitment during chronic liver injury, chemokines can directly affect the function of hepatic stellate cells within the liver. Up to now, nine of the 19 known chemokine receptors have been characterised on stellate cells. Stimulation of most of these receptors with specific ligands leads to increased migration and proliferation of stellate cells, suggesting predominantly profibrotic effects of chemokines. The only chemokine receptor with potential antifibrotic effects identified so far is CXCR3. Notably, hepatic stellate cells are not only a target but also a source of chemokines which contributes to the direct interaction between stellate cells and other cells during fibrogenesis. The further characterisation of this interaction will yield new therapeutic options for the treatment of chronic liver diseases. In this respect chemokines are a valuable target as oral chemokine receptor antagonists have already been licensed for human use.

Schlüsselwörter

Leber - Virushepatitis - Hepatitis C

Key words

liver - viral hepatitis - hepatitis C

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