STAT3 protects from liver injury and fibrosis in a mouse model of sclerosing cholangitis.

Background and aims: Signal transducer and activator of transcription 3 (Stat3) is the main mediator of interleukin-6 type cytokine signaling required for hepatocyte proliferation and hepatoprotection but its role in sclerosing cholangitis (SC) and other cholestatic liver diseases remains unresolved. Methods: We investigated the role of Stat3 in inflammation-induced cholestatic liver injury and used mice lacking the multidrug resistance gene 2 (mdr2-/-) as a model for SC. Results: We demonstrate that conditional inactivation of stat3 in hepatocytes and cholangiocytes (stat3hc) of mdr2-/- mice strongly aggravated bile acid-induced liver injury and fibrosis. Similarly, stat3hc mice are more sensitive to cholic acid feeding than control mice. Global gene expression analysis demonstrated that hepatoprotective signals via epidermal growth factor and insulin-like growth factor 1 are affected upon loss of Stat3. Conclusions: Our data suggest that Stat3 protects cholangiocytes and hepatocytes from bile acid-induced damage thereby preventing liver fibrosis in cholestatic diseases.

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Mair M, Zollner G, Schneller D, Musteanu M, Fickert P, Gumhold J, Schuster C, Fuchsbichler A, Bilban M, Tauber S, Esterbauer H, Kenner L, Poli V, Blaas L, Kornfeld JW, Casanova E, Mikulits W, Trauner M, Eferl R