Loss of interleukin-12 modifies the pro-inflammatory response but does not prevent duct obstruction in experimental biliary atresia.
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.
Mohanty
Sujit Kumar
SK
Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. sujit.mohanty@cchmc.org
Shivakumar
Pranavkumar
P
Sabla
Gregg
G
Bezerra
Jorge A
JA
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
D016207:Cytokines; C034477:RNA primers; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D012313:RNA