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

Sören V Siegmund,Percy A Knolle,Christian Kuntzen,Robert F Schwabe,Ekihiro Seki,Frank A Schildberg,Christian P Strassburg,Hiroshi Uchinami,Monika Schlosser,Samuele De Minicis

doi:10.1371/journal.pone.0150893

Sören V Siegmund, Percy A Knolle + Show 8 more

Open Access

https://doi.org/10.1371/journal.pone.0150893

Copy DOI

Journal: PloS one	Publication Date: Mar 3, 2016
Citations: 94	License type: CC BY 4.0

Affiliation: University of Bonn, Columbia University

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.

Highlights

Serum amyloid A (SAA) is a 12.5 kd acute phase protein which is highly conserved among all vertebrate species [1,2,3]
To assess whether SAA may influence the fibrogenic response in the liver, we determined its effect on proinflammatory and anti-apoptotic pathways in cultured hepatic stellate cells (HSCs), which are believed to play an essential role in HSC activation and perpetuation [29, 30]
The present study provides evidence that SAA modulates fibrogenic responses in the liver by inducing proliferation and inflammation in HSCs under some conditions and by promoting HSC cell death under other conditions

Summary

Introduction

Serum amyloid A (SAA) is a 12.5 kd acute phase protein which is highly conserved among all vertebrate species [1,2,3]. Hepatic acute-phase SAA production is stimulated by LPS and TNFα in a NFκB dependent manner, and accounts for up to 2.5% of protein produced in inflamed liver in humans and up to 10% in other species. We investigate whether SAA may be involved in a potential crosstalk between hepatocytes as its major producing cell type and hepatic stellate cells (HSCs). HSCs undergo an activation process to become the predominant extracellular matrix producing cell population [17, 18]. We demonstrate that SAA levels are strongly elevated in 2 mouse models of hepatic fibrosis, and that SAA elicits inflammation, proliferation and apoptosis in HSCs suggesting SAA as a potential mediator of hepatocyteHSC crosstalk in the injured liver

Experimental Procedures

Results

Discussion