IKK1 and IKK2 cooperate to maintain bile duct integrity in the liver

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 B kinases, IKK1/IKK␣ and IKK2/IKK␤, 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 I B kinases in mediating canonical NF-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-B signaling together with inhibition of IKK1-specific functions affecting the bile-blood barrier. These results reveal a novel function of the two I B kinases in cooperatively regulating liver immune homeostasis and bile duct integrity and suggest that IKK signaling may be implicated in human biliary diseases.cholangitis ͉ inflammation ͉ liver disease ͉ mouse models ͉ signal transduction

A single NFκB system for both canonical and non-canonical signaling

“…The fact that the IKK2 knockout [6] and the RelA knockout [7] showed a similar phenotype led to the broadly accepted model of a signaling axis of NEMO-IKK2-RelA, termed the canonical pathway. However, recent work suggests that IKK1 plays a role in the canonical pathway as well, and may compensate for the loss of IKK2 within the NEMO-dependent kinase [8]. Conversely, NEMOindependent IKK2 functions have also been suggested [9].…”

Acute inflammation regulates neuroregeneration through the NF-κB pathway in olfactory epithelium

“…TNFR1 (54) and TNFR2 (55) knockout mice were purchased from Jackson Laboratories. The floxed RelA line (35) was kindly provided by Mollie K. Meffert, Johns Hopkins Medicine, Baltimore. Krt5-Cre transgenic line (6) in which Cre recombinase is driven by the HBC specific Krt5 promoter was crossed to RelA flox/flox mice to generate RelA deletion in HBCs.…”

“…To study NF-κB signaling and its importance in olfactory neuroepithelium we generated mice in which cre mediated selective deletion of exons 2-4 of RelA (35) in the HBC population and permanently labeled those cells with a td-Tomato reporter (Krt5cre/RelA flox/flox /Rosa26-stop flox/flox -td-Tomato). RelA immunostaining revealed expression in all cell types of the olfactory mucosa (Fig.…”

NF-κB and STAT3 – key players in liver inflammation and cancer

“…Mice with hepatocytes-specific ablation of IKKβ [31][32][33]. Like Ikkβ ∆hep mice, mice deleted of RelA in hepatocytes (RelA ∆hep mice) are also healthy unless challenged and exposed to TNF.…”