Inflammatory disease and cancer with a decrease in Kupffer cell numbers in Nucling-knockout mice.
Nucling is a stress-inducible protein associated with apoptosomes. The cytochrome c-triggered formation of apoptosomes represents a key-initiating event in apoptosis. We have recently reported that Nucling regulates the apoptotic pathway by controlling the activation of NF-kappaB as well. Here we show that hepatocellular carcinoma (HCC) arising spontaneously against a background of hepatitis occurred more frequently in Nucling-knockout (KO) mice than wild-type (WT) mice. Biochemical serum testing revealed potential liver dysfunction with hypercholesterolemia in Nucling-KO males. In the background of Nucling-KO mice, we observed the up-regulation of TNFalpha, spontaneous NF-kappaB-activation and the induction of galectin-3 expression in liver. In addition, we observed a decrease in the number of Kupffer cells (KCs) in the KO mice. KCs are important for the hepatic immune system, acting as phagocytes or antigen-presenting cells (APCs). We found that KCs in Nucling-KO mice were apoptotic possibly through the up-regulation of TNFalpha. These observations indicate that Nucling is important for the regulation of NF-kappaB signals in liver. We propose that Nucling deficiency could be a powerful tool to reveal the NF-kappaB-related molecular networks leading to hepatitis and HCC development.
Sakai
Takashi
T
The Institute for Enzyme Research, The University of Tokushima, Kuramoto-cho, Tokushima, Japan.
Liu
Li
L
Teng
Xichuan
X
Ishimaru
Naozumi
N
Mukai-Sakai
Rika
R
Tran
Nam Hoang
NH
Kim
Sun Mi
SM
Sano
Nobuya
N
Hayashi
Yoshio
Y
Kaji
Ryuji
R
Fukui
Kiyoshi
K
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D002251:Carbon Tetrachloride / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D024202:Electrophoretic Mobility Shift Assay; D005434:Flow Cytometry; D006505:Hepatitis / Q000150:complications / Q000235:genetics* / Q000473:pathology; D007150:Immunohistochemistry; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D007728:Kupffer Cells / Q000473:pathology*; D008113:Liver Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D011230:Precancerous Conditions / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D002273:Carcinogens; D008565:Membrane Proteins; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C483107:Uaca protein, mouse; D002251:Carbon Tetrachloride