Hepatocyte apoptotic bodies encasing nonstructural HCV proteins amplify hepatic stellate cell activation: implications for chronic hepatitis C.
Chronic hepatitis C infection leads to increased hepatocyte apoptosis. Because engulfment of apoptotic bodies (ABs) by hepatic stellate cells (HSC) is profibrogenic, we compared the effects of ABs derived from hepatitis C virus (HCV)-negative vs HCV-infected (Con1+) Huh7 hepatoblastoma cells on fibrogenic and activation-related mRNA expression by a human HSC line (LX2). Uptake of Huh7(Con1+) ABs by LX2 cells dose dependently upregulated profibrotic genes (COL1A1, TGFB1; TIMP1; TIMP2). When normalized to the apoptotic cytokeratin-18 M30 neoepitope, HCV(+) ABs exhibited a more pronounced effect than HCV(-) ABs. In contrast, neither noningested ABs nor nucleic acids obtained from Huh7, Huh7(Con1+) or HepG2 cells triggered those AB-dependent effects. Both the engulfment of Huh7(Con1+) ABs and their effects were partially blocked by masking of phosphatidylserine with annexin V and completely inhibited by the class-A scavenger receptor ligand, polyinosinic acid. Our findings demonstrate that AB uptake stimulates HSCs and indicate that HCV infection leads to amplified fibrogenic mRNA expression and enhanced HSC activation.
Gieseler
R K
RK
Department of Gastroenterology and Hepatology, University Hospital Essen, Hufelandstrasse 55, Essen, Germany.
Marquitan
G
G
Schlattjan
M
M
Sowa
J-P
JP
Bechmann
L P
LP
Timm
J
J
Roggendorf
M
M
Gerken
G
G
Friedman
S L
SL
Canbay
A
A
D000199:Actins / Q000096:biosynthesis; D017304:Annexin A5 / Q000378:metabolism; D000906:Antibodies / Q000378:metabolism; D017209:Apoptosis; D002460:Cell Line; D045744:Cell Line, Tumor; D024042:Collagen Type I / Q000096:biosynthesis / Q000235:genetics; D000090602:Collagen Type I, alpha 1 Chain; D016174:Hepacivirus / Q000502:physiology*; D055166:Hepatic Stellate Cells / Q000473:pathology* / Q000502:physiology; D018936:Hepatitis C Antigens; D019698:Hepatitis C, Chronic / Q000378:metabolism / Q000473:pathology*; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D006801:Humans; D053538:Keratin-18 / Q000235:genetics; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000378:metabolism / Q000821:virology; D010718:Phosphatidylserines / Q000378:metabolism; D011069:Poly I / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000096:biosynthesis; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis / Q000235:genetics; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis / Q000235:genetics; D017361:Viral Nonstructural Proteins
C541116:ACTA2 protein, human; D000199:Actins; D017304:Annexin A5; D000906:Antibodies; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D018936:Hepatitis C Antigens; D053538:Keratin-18; D010718:Phosphatidylserines; D012333:RNA, Messenger; C508960:TGFB1 protein, human; C560822:TIMP1 protein, human; C560823:TIMP2 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D053773:Transforming Growth Factor beta1; D017361:Viral Nonstructural Proteins; D019716:Tissue Inhibitor of Metalloproteinase-2; D011069:Poly I; D020797:Receptor, Platelet-Derived Growth Factor beta