Mohanty Sujit Kumar, Shivakumar Pranavkumar, Sabla Gregg, Bezerra Jorge A
Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
BMC Gastroenterol. 2006 Apr 19;6:14. doi: 10.1186/1471-230X-6-14.
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.
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.
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.
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.
患有胆道闭锁的婴儿以及感染轮状病毒（RRV）的新生小鼠的肝脏中，γ干扰素（IFNγ）和白细胞介素（IL）-12的表达增加。虽然IFNγ的表达调节淋巴细胞对肝外胆管的阻塞，但IL-12在胆道阻塞发病机制中的作用尚不清楚。基于IL-12作为关键促炎细胞因子的作用，我们推测IL-12的缺失可预防肝外胆管阻塞。
在1日龄时给IL12基因敲除（IL-12KO）小鼠和野生型小鼠注射RRV或生理盐水，并监测症状的发展。在第3、7和14天通过实时PCR和流式细胞术确定细胞和分子表型。
IL-12KO小鼠感染RRV后出现生长衰竭、黄疸/无胆汁粪便，且存活率降低，与野生型小鼠相似。IL-12KO小鼠肝外胆管有明显的富含中性粒细胞的门脉炎症和上皮脱落。IL-12的缺失降低了但并未消除肝脏中IFNγ的表达，TNFα、IFNα、IFNβ的表达显著增加，而IL-4和IL-5的表达降低。
IL-12的缺失并未改变实验性胆道闭锁中胆管阻塞的进展。然而，炎症反应主要以中性粒细胞为主，且在缺乏IL-12的情况下表现为Th1反应。
