IKK1 and IKK2 cooperate to maintain bile duct integrity in the liver.
Inflammatory destruction of intrahepatic bile ducts is a common cause of vanishing bile duct syndrome and cholestasis, often progressing to biliary cirrhosis and liver failure. However, the molecular mechanisms underlying the pathogenesis of inflammatory biliary disease are poorly understood. Here, we show that the two IkappaB kinases, IKK1/IKKalpha and IKK2/IKKbeta, display distinct collaborative and specific functions that are essential to protect the liver from cytokine toxicity and bile duct disease. Combined conditional ablation of IKK1 and IKK2, but not of each kinase alone, sensitized the liver to in vivo LPS challenge, uncovering a redundant function of the two IkappaB kinases in mediating canonical NF-kappaB signaling in hepatocytes and protecting the liver from TNF-induced failure. Unexpectedly, mice with combined ablation of IKK1 and IKK2 or IKK1 and NEMO spontaneously developed severe jaundice and fatal cholangitis characterized by inflammatory destruction of small portal bile ducts. This bile duct disease was caused by the combined impairment of canonical NF-kappaB signaling together with inhibition of IKK1-specific functions affecting the bile-blood barrier. These results reveal a novel function of the two IkappaB kinases in cooperatively regulating liver immune homeostasis and bile duct integrity and suggest that IKK signaling may be implicated in human biliary diseases.
Luedde
Tom
T
Institute for Genetics, Centre for Molecular Medicine (CMMC), and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Zülpicher Strasse 47, 50674 Cologne, Germany.
Heinrichsdorff
Jan
J
de Lorenzi
Rossana
R
De Vos
Rita
R
Roskams
Tania
T
Pasparakis
Manolis
M
D000818:Animals; D001649:Bile Duct Diseases / Q000209:etiology* / Q000473:pathology; D001652:Bile Ducts / Q000201:enzymology* / Q000502:physiology; D022781:Hepatocytes / Q000378:metabolism; D051550:I-kappa B Kinase / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism
D008070:Lipopolysaccharides; D016328:NF-kappa B; D051550:I-kappa B Kinase