Signal transducer and activator of transcription 3 protects from liver injury and fibrosis in a mouse model of sclerosing cholangitis

Markus Mair, Gernot Zollner, Doris Schneller, Monica Musteanu, Peter Fickert, Judith Gumhold, Christian Schuster, Andrea Fuchsbichler, Martin Bilban, Stefanie Tauber, Harald Esterbauer, Lukas Kenner, Valeria Poli, Leander Blaas, Jan Wilhelm Kornfeld, Emilio Casanova, Wolfgang Mikulits, Michael Trauner, Robert Eferl

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

BACKGROUND & 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 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 show that conditional inactivation of Stat3 in hepatocytes and cholangiocytes (stat3(Deltahc)) of mdr2(-/-) mice strongly aggravated bile acid-induced liver injury and fibrosis. A similar phenotype was observed in mdr2(-/-) mice lacking interleukin-6 production. Biochemical and molecular characterization suggested that Stat3 exerts hepatoprotective functions in both hepatocytes and cholangiocytes. Loss of Stat3 led to increased expression of tumor necrosis factor alpha, which might reduce the barrier function of bile ducts. Moreover, Stat3-deficient hepatocytes displayed up-regulation of bile acid biosynthesis genes and down-regulation of hepatoprotective epidermal growth factor receptor and insulin-like growth factor 1 signaling pathways. Consistently, stat3(Deltahc) mice were more sensitive to cholic acid-induced liver damage than control mice.

CONCLUSIONS: Our data suggest that Stat3 prevents cholestasis and liver damage in sclerosing cholangitis via regulation of pivotal functions in hepatocytes and cholangiocytes.

OriginalsprogEngelsk
TidsskriftGastroenterology
Vol/bind138
Udgave nummer7
Sider (fra-til)2499-508
Antal sider10
ISSN0016-5085
DOI
StatusUdgivet - jun. 2010

Fingeraftryk

Sclerosing Cholangitis
Liver Cirrhosis
Hepatocytes
MDR Genes
Wounds and Injuries
Liver
Epidermal Growth Factor Receptor
Liver Diseases
Interleukin-6
Up-Regulation
Down-Regulation
Tumor Necrosis Factor-alpha

Bibliografisk note

Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

Citer dette

Mair, Markus ; Zollner, Gernot ; Schneller, Doris ; Musteanu, Monica ; Fickert, Peter ; Gumhold, Judith ; Schuster, Christian ; Fuchsbichler, Andrea ; Bilban, Martin ; Tauber, Stefanie ; Esterbauer, Harald ; Kenner, Lukas ; Poli, Valeria ; Blaas, Leander ; Kornfeld, Jan Wilhelm ; Casanova, Emilio ; Mikulits, Wolfgang ; Trauner, Michael ; Eferl, Robert. / Signal transducer and activator of transcription 3 protects from liver injury and fibrosis in a mouse model of sclerosing cholangitis. I: Gastroenterology. 2010 ; Bind 138, Nr. 7. s. 2499-508.
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title = "Signal transducer and activator of transcription 3 protects from liver injury and fibrosis in a mouse model of sclerosing cholangitis",
abstract = "BACKGROUND & 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 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 show that conditional inactivation of Stat3 in hepatocytes and cholangiocytes (stat3(Deltahc)) of mdr2(-/-) mice strongly aggravated bile acid-induced liver injury and fibrosis. A similar phenotype was observed in mdr2(-/-) mice lacking interleukin-6 production. Biochemical and molecular characterization suggested that Stat3 exerts hepatoprotective functions in both hepatocytes and cholangiocytes. Loss of Stat3 led to increased expression of tumor necrosis factor alpha, which might reduce the barrier function of bile ducts. Moreover, Stat3-deficient hepatocytes displayed up-regulation of bile acid biosynthesis genes and down-regulation of hepatoprotective epidermal growth factor receptor and insulin-like growth factor 1 signaling pathways. Consistently, stat3(Deltahc) mice were more sensitive to cholic acid-induced liver damage than control mice.CONCLUSIONS: Our data suggest that Stat3 prevents cholestasis and liver damage in sclerosing cholangitis via regulation of pivotal functions in hepatocytes and cholangiocytes.",
keywords = "ATP Binding Cassette Transporter, Subfamily B/physiology, Animals, Bile Acids and Salts/toxicity, Cell Proliferation, Cholangitis, Sclerosing/complications, Cytoprotection, Liver/drug effects, Liver Cirrhosis, Experimental/prevention & control, Liver Regeneration, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, STAT3 Transcription Factor/physiology, Tumor Necrosis Factor-alpha/biosynthesis",
author = "Markus Mair and Gernot Zollner and Doris Schneller and Monica Musteanu and Peter Fickert and Judith Gumhold and Christian Schuster and Andrea Fuchsbichler and Martin Bilban and Stefanie Tauber and Harald Esterbauer and Lukas Kenner and Valeria Poli and Leander Blaas and Kornfeld, {Jan Wilhelm} and Emilio Casanova and Wolfgang Mikulits and Michael Trauner and Robert Eferl",
note = "Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.",
year = "2010",
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doi = "10.1053/j.gastro.2010.02.049",
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pages = "2499--508",
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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 2010, 'Signal transducer and activator of transcription 3 protects from liver injury and fibrosis in a mouse model of sclerosing cholangitis', Gastroenterology, bind 138, nr. 7, s. 2499-508. https://doi.org/10.1053/j.gastro.2010.02.049

Signal transducer and activator of transcription 3 protects from liver injury and fibrosis in a mouse model of sclerosing cholangitis. / Mair, Markus; Zollner, Gernot; Schneller, Doris; Musteanu, Monica; Fickert, Peter; Gumhold, Judith; Schuster, Christian; Fuchsbichler, Andrea; Bilban, Martin; Tauber, Stefanie; Esterbauer, Harald; Kenner, Lukas; Poli, Valeria; Blaas, Leander; Kornfeld, Jan Wilhelm; Casanova, Emilio; Mikulits, Wolfgang; Trauner, Michael; Eferl, Robert.

I: Gastroenterology, Bind 138, Nr. 7, 06.2010, s. 2499-508.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Signal transducer and activator of transcription 3 protects from liver injury and fibrosis in a mouse model of sclerosing cholangitis

AU - Mair, Markus

AU - Zollner, Gernot

AU - Schneller, Doris

AU - Musteanu, Monica

AU - Fickert, Peter

AU - Gumhold, Judith

AU - Schuster, Christian

AU - Fuchsbichler, Andrea

AU - Bilban, Martin

AU - Tauber, Stefanie

AU - Esterbauer, Harald

AU - Kenner, Lukas

AU - Poli, Valeria

AU - Blaas, Leander

AU - Kornfeld, Jan Wilhelm

AU - Casanova, Emilio

AU - Mikulits, Wolfgang

AU - Trauner, Michael

AU - Eferl, Robert

N1 - Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

PY - 2010/6

Y1 - 2010/6

N2 - BACKGROUND & 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 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 show that conditional inactivation of Stat3 in hepatocytes and cholangiocytes (stat3(Deltahc)) of mdr2(-/-) mice strongly aggravated bile acid-induced liver injury and fibrosis. A similar phenotype was observed in mdr2(-/-) mice lacking interleukin-6 production. Biochemical and molecular characterization suggested that Stat3 exerts hepatoprotective functions in both hepatocytes and cholangiocytes. Loss of Stat3 led to increased expression of tumor necrosis factor alpha, which might reduce the barrier function of bile ducts. Moreover, Stat3-deficient hepatocytes displayed up-regulation of bile acid biosynthesis genes and down-regulation of hepatoprotective epidermal growth factor receptor and insulin-like growth factor 1 signaling pathways. Consistently, stat3(Deltahc) mice were more sensitive to cholic acid-induced liver damage than control mice.CONCLUSIONS: Our data suggest that Stat3 prevents cholestasis and liver damage in sclerosing cholangitis via regulation of pivotal functions in hepatocytes and cholangiocytes.

AB - BACKGROUND & 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 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 show that conditional inactivation of Stat3 in hepatocytes and cholangiocytes (stat3(Deltahc)) of mdr2(-/-) mice strongly aggravated bile acid-induced liver injury and fibrosis. A similar phenotype was observed in mdr2(-/-) mice lacking interleukin-6 production. Biochemical and molecular characterization suggested that Stat3 exerts hepatoprotective functions in both hepatocytes and cholangiocytes. Loss of Stat3 led to increased expression of tumor necrosis factor alpha, which might reduce the barrier function of bile ducts. Moreover, Stat3-deficient hepatocytes displayed up-regulation of bile acid biosynthesis genes and down-regulation of hepatoprotective epidermal growth factor receptor and insulin-like growth factor 1 signaling pathways. Consistently, stat3(Deltahc) mice were more sensitive to cholic acid-induced liver damage than control mice.CONCLUSIONS: Our data suggest that Stat3 prevents cholestasis and liver damage in sclerosing cholangitis via regulation of pivotal functions in hepatocytes and cholangiocytes.

KW - ATP Binding Cassette Transporter, Subfamily B/physiology

KW - Animals

KW - Bile Acids and Salts/toxicity

KW - Cell Proliferation

KW - Cholangitis, Sclerosing/complications

KW - Cytoprotection

KW - Liver/drug effects

KW - Liver Cirrhosis, Experimental/prevention & control

KW - Liver Regeneration

KW - Mice

KW - Mice, Inbred BALB C

KW - Mice, Inbred C57BL

KW - STAT3 Transcription Factor/physiology

KW - Tumor Necrosis Factor-alpha/biosynthesis

U2 - 10.1053/j.gastro.2010.02.049

DO - 10.1053/j.gastro.2010.02.049

M3 - Journal article

C2 - 20193684

VL - 138

SP - 2499

EP - 2508

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

IS - 7

ER -