Title: IKK1 and IKK2 cooperate to maintain bile duct integrity in the liver
Authors: Luedde, Tom
Heinrichsdorff, Jan
de Lorenzi, Rossana
De Vos, Rita
Roskams, Tania
Pasparakis, Manolis # ×
Issue Date: Jul-2008
Publisher: Natl acad sciences
Series Title: Proceedings of the national academy of sciences of the united states of america vol:105 issue:28 pages:9733-9738
Abstract: 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 I kappa B kinases, IKK1/IKK alpha and IKK2/IKK beta, 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 LIPS challenge, uncovering a redundant function of the two I kappa B kinases in mediating canonical NF-kappa B 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-kappa B signaling together with inhibition of IKK1-specific functions affecting the bile-blood barrier. These results reveal a novel function of the two I kappa B kinases in cooperatively regulating liver immune homeostasis and bile duct integrity and suggest that IKK signaling may be implicated in human biliary diseases.
ISSN: 0027-8424
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Translational Cell & Tissue Research
× corresponding author
# (joint) last author

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