title: Loss of interleukin-12 modifies the pro-inflammatory response but does not prevent duct obstruction in experimental biliary atresia.
abstract: BACKGROUND
  Livers of infants with biliary atresia and of neonatal mice infected with rotavirus (RRV) have increased expression of interferon-gamma (IFNgamma) and interleukin (IL)-12. While the expression of IFNgamma regulates the obstruction of extrahepatic bile ducts by lymphocytes, the role of IL-12 in the pathogenesis of biliary obstruction is unknown. Based on the role of IL-12 as a key proinflammatory cytokine, we hypothesized that loss of IL-12 prevents the obstruction of extrahepatic bile ducts.
  
  
  METHODS
  IL12-knockout (IL-12KO) and wild type mice were injected with RRV or saline at day 1 of age and monitored for the development of symptoms. The cellular and molecular phenotypes were determined at days 3, 7, and 14 by real-time PCR and flow cytometry.
  
  
  RESULTS
  RRV infection of IL-12KO mice resulted in growth failure, jaundice/acholic stools, and decreased survival similar to wild-type mice. IL-12KO mice had a remarkable neutrophil-rich portal inflammation and epithelial sloughing of extrahepatic bile ducts. Loss of IL-12 decreased but did not abolish the hepatic expression of IFNgamma, displayed a remarkable increase in expression of TNFalpha, IFNalpha, IFNbeta and decreased expression of IL-4 and IL-5.
  
  
  CONCLUSIONS
  Loss of IL-12 did not modify the progression of bile duct obstruction in experimental biliary atresia. However, the inflammatory response was predominantly neutrophil-based and displayed a Th1 response in the absence of IL-12.
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. sujit.mohanty@cchmc.org
authors.forename: Sujit Kumar
authors.initials: SK
authors.lastname: Mohanty
authors.forename: Pranavkumar
authors.initials: P
authors.lastname: Shivakumar
authors.forename: Gregg
authors.initials: G
authors.lastname: Sabla
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Bezerra
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001656:Biliary Atresia / Q000276:immunology* / Q000473:pathology / Q000821:virology; D002779:Cholestasis / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000473:pathology; D008214:Lymphocytes / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009504:Neutrophils / Q000502:physiology; D012313:RNA; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012401:Rotavirus; D012400:Rotavirus Infections / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016207:Cytokines; C034477:RNA primers; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D012313:RNA