Hepatocyte-specific inhibitor-of-κB-kinase deletion triggers the innate immune response and promotes earlier cell proliferation during liver regeneration

Medical Clinic III, University Hospital Aachen (RWTH), Aachen, Germany.
Hepatology (Impact Factor: 11.06). 06/2008; 47(6):2036-50. DOI: 10.1002/hep.22264
Source: PubMed

ABSTRACT Nuclear factor kappaB (NF-kappaB) is one of the main transcription factors involved in liver regeneration after partial hepatectomy (PH). It is activated upon IkappaB phosphorylation by the IkappaB kinase (IKK) complex comprising inhibitor of kappaB kinase 1 (IKK1), inhibitor of kappaB kinase 2 (IKK2), and nuclear factor-B essential modifier (NEMO). We studied the impact of hepatocyte-specific IKK2 deletion during liver regeneration. A 70% PH was performed on IKK2(f/f) (wild-type) and IKK2DeltaLPCmice (hepatocyte-specific IKK2 knockout mice). PH in IKK2DeltaLPC compared with IKK2(f/f) mice resulted in weaker and delayed NF-kappaB activation in hepatocytes, while nonparenchymal liver cells showed earlier NF-kappaB activation and higher tumor necrosis factor expression. Additionally, these animals showed increased and earlier serum amyloid A and chemotactic cytokine L-1 levels followed by enhanced polymorphonuclear cell recruitment to the liver. These results correlated with earlier Jun kinase activity, c-myc expression, and matrix metalloproteinase-9 activity, suggesting earlier priming in IKK2DeltaLPC mice after PH. These data preceded a more rapid cell cycle progression and earlier hepatocyte proliferation as evidenced through cyclin and 5-bromo-2-deoxyuridine analysis. Interestingly, despite faster G(1)/S progression, IKK2DeltaLPC mice exhibited an enduring mitosis phase, because mitotic bodies were still observed at later stages after PH. CONCLUSION: We demonstrate that PH in IKK2DeltaLPC mice triggers a more rapid and pronounced inflammatory response in nonparenchymal liver cells, which triggers earlier hepatocyte proliferation.

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    • "The roles played by NF-κB and JNK during liver regeneration have previously been investigated, although the details remain controversial. Absence of NF-κB activation in Kupffer cell-depleted mice impaired liver regeneration after PH [1], whereas deletion of a hepatocyte-specific inhibitor of B kinase (IKK) promoted earlier hepatocyte proliferation [21]. Conditional c-jun KO mice exhibited impaired liver regeneration [3], and inhibition of JNK delayed hepatocyte proliferation [27]. "
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    ABSTRACT: Vitamin D3 up-regulated protein 1 (VDUP1) is a potent growth suppressor that, when overexpressed, inhibits tumor cell proliferation and cell cycle progression. In a previous study, we showed that VDUP1 knockout (KO) mice exhibited accelerated liver regeneration because such animals could effectively control the expression of cell cycle regulators that drive the G1-to-S phase progression. In the present work, we further investigated the role played by VDUP1 in initial priming of liver regeneration. VDUP1 KO and wild-type (WT) mice were subjected to 70% partial hepatectomy (PH) and sacrificed at different times after surgery. The hepatic levels of TNF-α and IL-6 increased after PH, but there were no significant differences between VDUP1 KO and WT mice. Nuclear factor-κB (NF-κB), c-Jun-N-terminal kinase (JNK), and signal transducer and activator of transcription 3 (STAT-3) were activated much earlier and to a greater extent in VDUP1 KO mice after PH. A single injection of TNF-α or IL-6 caused rapid activation of JNK and STAT-3 expression in both mice, but the responses were stronger and more sustained in VDUP1 KO mice. In conclusion, our findings provide evidence that VDUP1 plays a role in initiation of liver regeneration.
    Journal of veterinary science (Suwŏn-si, Korea) 06/2013; 14(3). DOI:10.4142/jvs.2013.14.3.257 · 1.16 Impact Factor
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    • "Studies of these mice so far reveal diverse cell type-specific roles of IKKβ. In keratinocytes, IKKβ acts to maintain the immune homeostasis of the skin [7], [8]; in neurons, it inhibits sensory neuron excitability [9]; in hepatocytes, it suppresses cell proliferation [10], [11]; and in mammary epithelial cells, IKKβ potentiates apoptosis that leads to mammary gland involution [12]. "
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    ABSTRACT: The IKKβ is known to regulate transcription factor NF-κB activation leading to inflammatory responses. Recent gene knockout studies have shown that IKKβ can orchestrate local inflammatory responses and regulate homeostasis of epithelial tissues. To investigate whether IKKβ has an intrinsic role in epithelial cells, we established an in vivo system in the immune privileged corneal epithelium. We generated triple transgenic Krt12(rtTA/rtTAt)/tet-O-Cre/Ikkβ(F/F) (Ikkβ(ΔCE/ΔCE)) mice by crossing the Krt12-rtTA knock-in mice, which express the reverse tetracycline transcription activator in corneal epithelial cells, with the tet-O-Cre and Ikkβ(F/F) mice. Doxycycline-induced IKKβ ablation occurred in corneal epithelial cells of triple transgenic Ikkβ(ΔCE/ΔCE) mice, but loss of IKKβ did not cause ocular abnormalities in fetal development and postnatal maintenance. Instead, loss of IKKβ significantly delayed healing of corneal epithelial debridement without affecting cell proliferation, apoptosis or macrophage infiltration. In vitro studies with human corneal epithelial cells (HCEpi) also showed that IKKβ was required for cytokine-induced cell migration and wound closure but was dispensable for cell proliferation. In both in vivo and in vitro settings, IKKβ was required for optimal activation of NF-κB and p38 signaling in corneal epithelial cells, and p38 activation is likely mediated through formation of an IKKβ-p38 protein complex. Thus, our studies in corneal epithelium reveal a previously un-recognized role for IKKβ in the control of epithelial cell motility and wound healing.
    PLoS ONE 01/2011; 6(1):e16132. DOI:10.1371/journal.pone.0016132 · 3.23 Impact Factor
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    • "This study also examined pharmacological inhibition of IKKβ, which enables to inhibit IKKβ activity in both hepatocytes and nonparenchymal cells. This treatment had little effect on the regenerative process [38], which corroborates the results from Chaisson et al. [36], but it does not support the results from Maeda et al., Yang et al., and us; NF-κB in Kupffer cells is critical in liver regeneration. "
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    ABSTRACT: While hepatocytes rarely undergo proliferation in normal livers, they quickly induce proliferation in response to loss of liver mass by toxin or inflammation-induced hepatocyte injury, trauma, or surgical resection, leading to a restoration of liver mass to its original size. Recent studies suggest that Toll-like receptor (TLR) signaling participates in this regenerative response. Myeloid differentiation factor (MyD88), a common adaptor molecule in the TLR, IL-1 and IL-18 receptor signaling, plays a key role, at least, in the early phase of liver regeneration. Currently, definite ligands which bind to TLRs and initiate this process are still unclear. TLRs stimulated by their corresponding ligands, as well as tumor necrosis factor (TNF) receptors (TNFRs), can activate downstream signal molecules, including transcription factor nuclear factor (NF)-κB and c-Jun N-terminal kinase (JNK). Previous studies have revealed the important role of TNF receptor signaling, NF-κB, and JNK in liver regeneration by using hepatocyte-specific gene-modified animals. This review will summarize the current knowledge of TLR signaling and their related molecules in liver regeneration. We will also discuss whether modulating these factors may become new therapeutic strategies to promote liver regeneration in various clinical situations.
    Gastroenterology Research and Practice 09/2010; 2010. DOI:10.1155/2010/598109 · 1.75 Impact Factor
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