Kupffer Cell Engulfment of Apoptotic Bodies Stimulates... : Hepatology (original) (raw)
Original Articles: Liver Biology And Pathobiology: PDF Only
Kupffer Cell Engulfment of Apoptotic Bodies Stimulates Death Ligand and Cytokine Expression
Canbay, Ali1; Feldstein, Ariel E.1; Higuchi, Hajime1; Werneburg, Nate1; Grambihler, Annette1; Bronk, Steve F.1; Gores, Gregory J. M.D.*,1
1_Division of Gastroenterology and Hepatology, Mayo Medical School, Clinic, and Foundation, Rochester, MN_
* Professor of Medicine, Mayo Medical School, Clinic, and Foundation, 200 First Street SW, Rochester, MN 55905. fax: 507–284–0762; E-mail: [email protected].
Received: 17 June 2003; Accepted: 24 August 2003
Abstract
Hepatocyte apoptosis by death receptors, hepatic inflammation, and fibrosis are prominent features of liver diseases. However, the link between these processes remains unclear. Our aim was to ascertain whether engulfment of apoptotic bodies by Kupffer cells promotes hepatic inflammation and fibrosis. Isolated murine Kupffer cells efficiently engulfed apoptotic bodies generated from UV–treated mouse hepatocytes. Engulfment of the apoptotic bodies, but not latex beads, stimulated Kupffer cell generation of death ligands, including Fas ligand, and tumor necrosis factor α (TNF–α). Both apoptotic body phagocytosis and death ligand generation were attenuated by gadolinium chloride, a Kupffer cell toxicant. Kupffer cells isolated from 3–day bile duct–ligated (BDL) mice were phenotypically similar to apoptotic body–“fed” Kupffer cells with enhanced death ligand expression; inhibition of hepatocyte apoptosis with a caspase inhibitor prevented this Kupffer cell activation. Consistent with a role for Kupffer cells in liver inflammation and fibrosis, gadolinium chloride attenuated neutrophil infiltration and markers for stellate cell activation. In conclusion, these findings support a model of cholestatic liver injury where Kupffer cell engulfment of apoptotic bodies promotes inflammation and fibrogenesis.
Copyright © 2003 American Association for the Study of Liver Diseases.