Transcription factor Fra-1 induces cholangitis and liver fibrosis.
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Transcription factor Fra-1 induces cholangitis and liver fibrosis. / Kireva, Trayana; Erhardt, Annette; Tiegs, Gisa; Tilg, Herbert; Denk, Helmut; Haybaeck, Johannes; Aigner, Elmar; Moschen, Alexander; Distler, Jörg H; Schett, Georg; Zwerina, Jochen.
In: HEPATOLOGY, Vol. 53, No. 4, 4, 2011, p. 1259-1269.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Transcription factor Fra-1 induces cholangitis and liver fibrosis.
AU - Kireva, Trayana
AU - Erhardt, Annette
AU - Tiegs, Gisa
AU - Tilg, Herbert
AU - Denk, Helmut
AU - Haybaeck, Johannes
AU - Aigner, Elmar
AU - Moschen, Alexander
AU - Distler, Jörg H
AU - Schett, Georg
AU - Zwerina, Jochen
PY - 2011
Y1 - 2011
N2 - Chronic diseases of the biliary system are common and may cause fibrosis and eventually progression to liver cirrhosis. The aim was to define a new mouse model of a cholangiopathy leading to liver fibrosis in fra-1tg mice. Liver pathology of fra-1tg mice was analyzed in detail by histology and flow cytometry. Transcript levels of fibrosis-related genes and matrix metalloproteinase (MMP) activities were quantified and immunohistochemical analysis additionally applied. The role of the immune system in this model was analyzed by crossing fra-1tg mice with rag2(-/-) mice. Furthermore, expression of Fra-1 in corresponding human liver diseases was investigated on transcription level and histologically. Fra-1tg mice spontaneously develop biliary fibrosis preceded by ductular proliferation and infiltration of inflammatory cells. Fra-1 protein is present in cholangiocytes and inflammatory cells within the liver. These findings were replicated in human biopsies of patients with advanced liver fibrosis. The inflammatory infiltrate showed a strong increase in activated T cells and decreased natural killer (NK), natural killer T cells (NKT), and B cells in fra-1tg mice as compared to wildtype mice. Moreover, fra-1tg mice develop biliary fibrosis with a time-dependent increase in hepatic collagen content and increase in relative messenger RNA (mRNA) expression of profibrotic genes. Attenuation but not complete prevention of collagen accumulation in liver was observed in the fra-1tg × rag2(-/-) mice. However, transplantation of fra-1tg bone marrow cells into wildtype mice could not induce disease. CONCLUSION: Fra-1tg mice spontaneously develop a progressive biliary disease. These mice are an attractive model for the investigation of cholangiopathies and their interaction with the immune system.
AB - Chronic diseases of the biliary system are common and may cause fibrosis and eventually progression to liver cirrhosis. The aim was to define a new mouse model of a cholangiopathy leading to liver fibrosis in fra-1tg mice. Liver pathology of fra-1tg mice was analyzed in detail by histology and flow cytometry. Transcript levels of fibrosis-related genes and matrix metalloproteinase (MMP) activities were quantified and immunohistochemical analysis additionally applied. The role of the immune system in this model was analyzed by crossing fra-1tg mice with rag2(-/-) mice. Furthermore, expression of Fra-1 in corresponding human liver diseases was investigated on transcription level and histologically. Fra-1tg mice spontaneously develop biliary fibrosis preceded by ductular proliferation and infiltration of inflammatory cells. Fra-1 protein is present in cholangiocytes and inflammatory cells within the liver. These findings were replicated in human biopsies of patients with advanced liver fibrosis. The inflammatory infiltrate showed a strong increase in activated T cells and decreased natural killer (NK), natural killer T cells (NKT), and B cells in fra-1tg mice as compared to wildtype mice. Moreover, fra-1tg mice develop biliary fibrosis with a time-dependent increase in hepatic collagen content and increase in relative messenger RNA (mRNA) expression of profibrotic genes. Attenuation but not complete prevention of collagen accumulation in liver was observed in the fra-1tg × rag2(-/-) mice. However, transplantation of fra-1tg bone marrow cells into wildtype mice could not induce disease. CONCLUSION: Fra-1tg mice spontaneously develop a progressive biliary disease. These mice are an attractive model for the investigation of cholangiopathies and their interaction with the immune system.
KW - Animals
KW - Humans
KW - Disease Models, Animal
KW - Mice
KW - Mice, Transgenic
KW - Liver/metabolism
KW - Chemokines/biosynthesis
KW - Cholangitis/chemically induced
KW - Fibrosis
KW - Liver Cirrhosis/chemically induced/pathology
KW - Proto-Oncogene Proteins c-fos/physiology
KW - Transcription Factor AP-1/physiology
KW - Animals
KW - Humans
KW - Disease Models, Animal
KW - Mice
KW - Mice, Transgenic
KW - Liver/metabolism
KW - Chemokines/biosynthesis
KW - Cholangitis/chemically induced
KW - Fibrosis
KW - Liver Cirrhosis/chemically induced/pathology
KW - Proto-Oncogene Proteins c-fos/physiology
KW - Transcription Factor AP-1/physiology
M3 - SCORING: Journal article
VL - 53
SP - 1259
EP - 1269
JO - HEPATOLOGY
JF - HEPATOLOGY
SN - 0270-9139
IS - 4
M1 - 4
ER -
