Premium
Interleukin‐1 receptor type I gene‐deficient bile duct–ligated mice are partially protected against endotoxin
Author(s) -
Sewnath Miguel E.,
Van Der Poll Tom,
Ten Kate Fiebo J. W.,
Van Noorden Cornelis J. F.,
Gouma Dirk J.
Publication year - 2002
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1053/jhep.2002.30272
Subject(s) - cholestasis , liver injury , cytokine , medicine , interleukin , endocrinology , bile duct , receptor , biology
Cholestatic liver injury is associated with an increased susceptibility toward endotoxin‐induced toxicity. To determine the role of interleukin 1 (IL‐1) herein, extrahepatic cholestasis was induced by bile duct ligation (bdl) in IL‐1 receptor type I gene‐deficient (IL‐1R −/− ) mice, which are unresponsive to IL‐1α and IL‐1β, and normal IL‐1R +/+ mice. Bdl elicited increases in hepatic IL‐1α and IL‐1β messenger RNA (mRNA) and protein. Hepatocellular injury at 2 weeks after bdl was similar in IL‐1R −/− and IL‐1R +/+ mice as shown by clinical chemistry and histopathology. Administration of endotoxin to cholestatic mice at 2 weeks after bdl was associated with enhanced cytokine release, more severe liver damage, and occurrence of death when compared with sham‐operated mice. Endotoxin effects in sham‐operated IL‐1R −/− and IL‐1R +/+ mice were largely similar, but cholestatic IL‐1R −/− mice were better protected against toxic effects of endotoxin, as reflected by lowered cytokine release, less profound liver injury, and reduced mortality. These data indicate that IL‐1α and IL‐1β are produced in the liver after bdl, but that these cytokines do not play a significant role in cholestatic liver damage; however, endogenous IL‐1 activity is an important denominator of enhanced endotoxin sensitivity that is observed during cholestasis induced by bdl.