TY - JOUR
T1 - Interleukin-1 receptor type I gene-deficient bile duct-ligated mice are partially protected against endotoxin
AU - Sewnath, Miguel E.
AU - van der Poll, Tom
AU - ten Kate, Fiebo J. W.
AU - van Noorden, Cornelis J. F.
AU - Gouma, Dirk J.
PY - 2002
Y1 - 2002
N2 - 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-IR-/-) mice, which are unresponsive to IL-1 alpha and IL-1 beta, and normal 1L-1R(+/+) mice. Bdl elicited increases in hepatic IL-1 alpha and IL-1 beta messenger RNA (mRNA) and protein. Hepatocellular injury at 2 weeks after bdl was similar in IL-IR-/- 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-1 alpha and IL-1 beta 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
AB - 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-IR-/-) mice, which are unresponsive to IL-1 alpha and IL-1 beta, and normal 1L-1R(+/+) mice. Bdl elicited increases in hepatic IL-1 alpha and IL-1 beta messenger RNA (mRNA) and protein. Hepatocellular injury at 2 weeks after bdl was similar in IL-IR-/- 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-1 alpha and IL-1 beta 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
U2 - https://doi.org/10.1053/jhep.2002.30272
DO - https://doi.org/10.1053/jhep.2002.30272
M3 - Article
C2 - 11786971
SN - 0270-9139
VL - 35
SP - 149
EP - 158
JO - Hepatology (Baltimore, Md.)
JF - Hepatology (Baltimore, Md.)
IS - 1
ER -