TRAIL Mediates Liver Injury by the Innate Immune System in the Bile Duct Ligated Mouse

ALISAN KAHRAMAN; FERNANDO J BARREYRO; STEVEN F BRONK; NATHAN W. WERNEBURG; JUSTIN L. MOTT; YUKO AKAZAWA; CHARLES L. HOWE; GREGORY J GORES

Essen, Germany

Simposio; LANDSBERG Symposium, 2007 “Mechanisms of Fibrogenesis in Chronic Liver Diseases”; 2007

Schloß Landsberg

The contribution of TRAIL, a death ligand expressed by cells of the innate immune system, to cholestatic liver injury has not been explored. Our aim was to ascertain if TRAIL contributes to liver injury in the bile duct ligated (BDL) mouse. C57/BL6 wildtype (wt), TRAIL knockout (TRAIL-/-) mice were used for these studies. Liver injury and fibrosis were examined 7 and 14 days after BDL, respectively. Hepatic TRAIL mRNA was 6-fold greater in BDL versus sham-operated wild-type animals (p < 0.01). The increased hepatic TRAIL expression was accompanied by an increase in liver accumulation of NK 1.1-positive NK and NKT cells, the predominant cell types expressing TRAIL. Consistent with a role for NK/NKT cells in this model of liver injury, stress ligands, MULT-1, H60, and RAE-1 subtypes, necessary for recognition of target cells by the NK activation receptor NKG2D were all increased >3-fold. Deletion of NK 1.1-positive cells reduced hepatic TRAIL mRNA expression and serum ALT values. As compared to sham-operated wild-type mice, BDL mice displayed a 13-fold increase in TUNEL and an 11-fold increase in caspase 3/7 positive hepatocytes (p < 0.01). The number of TUNEL and caspase 3/7-positive cells was reduced by > 80% in BDL TRAIL knockout animals (p < 0.05). Liver histology, number of bile infarcts, serum ALT values, hepatic fibrosis, and animal survival were also improved in BDL TRAIL-/- animals as compared to wt mice. In conclusion, these observations support a pivotal role for TRAIL in cholestatic liver injury mediated by NK 1.1-positive NK/NKT cells.