title: Serum Amyloid A Induces Inflammation, Proliferation and Cell Death in Activated Hepatic Stellate Cells.
abstract: Serum amyloid A (SAA) is an evolutionary highly conserved acute phase protein that is predominantly secreted by hepatocytes. However, its role in liver injury and fibrogenesis has not been elucidated so far. In this study, we determined the effects of SAA on hepatic stellate cells (HSCs), the main fibrogenic cell type of the liver. Serum amyloid A potently activated IκB kinase, c-Jun N-terminal kinase (JNK), Erk and Akt and enhanced NF-κB-dependent luciferase activity in primary human and rat HSCs. Serum amyloid A induced the transcription of MCP-1, RANTES and MMP9 in an NF-κB- and JNK-dependent manner. Blockade of NF-κB revealed cytotoxic effects of SAA in primary HSCs with signs of apoptosis such as caspase 3 and PARP cleavage and Annexin V staining. Serum amyloid A induced HSC proliferation, which depended on JNK, Erk and Akt activity. In primary hepatocytes, SAA also activated MAP kinases, but did not induce relevant cell death after NF-κB inhibition. In two models of hepatic fibrogenesis, CCl4 treatment and bile duct ligation, hepatic mRNA levels of SAA1 and SAA3 were strongly increased. In conclusion, SAA may modulate fibrogenic responses in the liver in a positive and negative fashion by inducing inflammation, proliferation and cell death in HSCs.
authors.affiliation: Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York, United States of America.|Dept. of Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Sören V
authors.initials: SV
authors.lastname: Siegmund
authors.affiliation: Dept. of Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Schlosser
authors.affiliation: Institutes of Molecular Medicine and Experimental Immunology, University of Bonn, Bonn, Germany.
authors.forename: Frank A
authors.initials: FA
authors.lastname: Schildberg
authors.affiliation: Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York, United States of America.
authors.forename: Ekihiro
authors.initials: E
authors.lastname: Seki
authors.affiliation: Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York, United States of America.
authors.forename: Samuele
authors.initials: S
authors.lastname: De Minicis
authors.affiliation: Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York, United States of America.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Uchinami
authors.affiliation: Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York, United States of America.
authors.forename: Christian
authors.initials: C
authors.lastname: Kuntzen
authors.affiliation: Institutes of Molecular Medicine and Experimental Immunology, University of Bonn, Bonn, Germany.
authors.forename: Percy A
authors.initials: PA
authors.lastname: Knolle
authors.affiliation: Dept. of Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Christian P
authors.initials: CP
authors.lastname: Strassburg
authors.affiliation: Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York, United States of America.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Schwabe
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D018946:Chemokine CCL5 / Q000235:genetics / Q000378:metabolism; D002779:Cholestasis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D007249:Inflammation; D008026:Ligation; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D008807:Mice, Inbred BALB C; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D061251:Primary Cell Culture; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000685:Serum Amyloid A Protein / Q000494:pharmacology*; D015398:Signal Transduction
chemical_list: C111835:CCL2 protein, human; C483024:CCL5 protein, human; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D016328:NF-kappa B; C521404:SAA1 protein, human; D000685:Serum Amyloid A Protein; D002251:Carbon Tetrachloride; D051057:Proto-Oncogene Proteins c-akt; D051550:I-kappa B Kinase; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048670:MAP Kinase Kinase 4; D020780:Matrix Metalloproteinase 9