Type-I but not type-II interferon receptor knockout mice are susceptible to biliary atresia.
The etiology of biliary atresia (BA) is not yet understood, but recent studies have shown inflammation with an up-regulated interferon (IFN) activity in the intra- and extrahepatic bile ducts of patients with BA. These findings support an inflammatory/infectious cause of BA as mimicked in our infective murine model. To study the role of the IFN receptors in our model, we used mice with inactivated INF-alpha/beta receptor A129, with inactivated IFN-gamma receptor G129, or inactivation of both interferon receptors AG129 as well as the wild type controls W129. Mice were infected with rotavirus within 48h of birth and 7 d postpartum. The incidence of BA in each group was determined during a 3 wk period. In the second week the virus load was measured. BA incidence was 76% in A129 and 67% in AG129 animals, whereas in the G129 group only 33% of the pups developed BA. The wild type presented with a BA-incidence of 15%, while 7 d old mice failed to develop BA. There was no significant difference in the virus load of the livers between the groups independent of clinical symptoms. In conclusion, inactivation of type I INF-receptor significantly increases the incidence of BA following postpartal rotavirus infection. This effect is independent of the presence of type II-INF-receptors. Thus, in our model a type I IFN-linked deregulation of the innate immune system appears to be crucial for the induction of biliary atresia.
Kuebler
Joachim F
JF
Department of Pediatric Surgery, Medical School Hannover, 30625 Hannover, Germany.
Czech-Schmidt
Gerard
G
Leonhardt
Johannes
J
Ure
Benno M
BM
Petersen
Claus
C
D000818:Animals; D001656:Biliary Atresia / Q000188:drug therapy / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D016898:Interferon-alpha / Q000627:therapeutic use; D051379:Mice; D018345:Mice, Knockout; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000502:physiology*; D015375:Receptors, Interleukin-2 / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000627:therapeutic use
D016898:Interferon-alpha; D017472:Receptors, Interleukin-1; D015375:Receptors, Interleukin-2; D011994:Recombinant Proteins