Serum Amyloid A Induces Inflammation, Proliferation and Cell Death in Activated Hepatic Stellate Cells

PLoS One. 2016 Mar 3;11(3):e0150893. doi: 10.1371/journal.pone.0150893. eCollection 2016.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carbon Tetrachloride
  • Cell Death / drug effects
  • Cell Proliferation / drug effects
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / metabolism
  • Chemokine CCL5 / genetics
  • Chemokine CCL5 / metabolism
  • Cholestasis / genetics*
  • Cholestasis / metabolism
  • Cholestasis / pathology
  • Disease Models, Animal
  • Gene Expression Regulation
  • Hepatic Stellate Cells / drug effects*
  • Hepatic Stellate Cells / metabolism
  • Hepatic Stellate Cells / pathology
  • Humans
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / metabolism
  • Inflammation
  • Ligation
  • Liver Cirrhosis / chemically induced
  • Liver Cirrhosis / genetics*
  • Liver Cirrhosis / metabolism
  • Liver Cirrhosis / pathology
  • MAP Kinase Kinase 4 / genetics
  • MAP Kinase Kinase 4 / metabolism
  • Male
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism
  • Mice, Inbred BALB C
  • Mitogen-Activated Protein Kinase 1 / genetics
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / genetics
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Primary Cell Culture
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Serum Amyloid A Protein / pharmacology*
  • Signal Transduction

Substances

  • CCL2 protein, human
  • CCL5 protein, human
  • Chemokine CCL2
  • Chemokine CCL5
  • NF-kappa B
  • SAA1 protein, human
  • Serum Amyloid A Protein
  • Carbon Tetrachloride
  • Proto-Oncogene Proteins c-akt
  • I-kappa B Kinase
  • MAPK1 protein, human
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • MAP Kinase Kinase 4
  • Matrix Metalloproteinase 9

Grants and funding

This work was funded by Deutsche Forschungsgemeinschaft (www.dfg.de), to SVS (TRR57-P15 and SI 1366/1-1); and American Gastroenterological Association (www.gastro.org), to RFS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.