PMID- 25088600
OWN - NLM
STAT- MEDLINE
DCOM- 20150211
LR  - 20231213
IS  - 1527-3350 (Electronic)
IS  - 0270-9139 (Print)
IS  - 0270-9139 (Linking)
VI  - 60
IP  - 6
DP  - 2014 Dec
TI  - Mouse hepatocyte overexpression of NF-kappaB-inducing kinase (NIK) triggers fatal 
      macrophage-dependent liver injury and fibrosis.
PG  - 2065-76
LID - 10.1002/hep.27348 [doi]
AB  - Damaged, necrotic, or apoptotic hepatocytes release damage-associated molecular 
      patterns that initiate sterile inflammation, and liver inflammation drives liver 
      injury and fibrosis. Here we identified hepatic nuclear factor kappa B 
      (NF-kappaB)-inducing kinase (NIK), a Ser/Thr kinase, as a novel trigger of fatal 
      liver inflammation. NIK is activated by a broad spectrum of stimuli. It was 
      up-regulated in injured livers in both mice and humans. In primary mouse 
      hepatocytes, NIK overexpression stimulated, independently of cell injury and 
      death, release of numerous chemokines and cytokines that activated bone 
      marrow-derived macrophages (BMDMs). BMDMs in turn secreted proapoptotic molecules 
      that stimulated hepatocyte apoptosis. Hepatocyte-specific expression of the NIK 
      transgene triggered massive liver inflammation, oxidative stress, hepatocyte 
      apoptosis, and liver fibrosis, leading to weight loss, hypoglycemia, and death. 
      Depletion of Kupffer cells/macrophages reversed NIK-induced liver destruction and 
      death. CONCLUSION: the hepatocyte NIK-liver immune cell axis promotes liver 
      inflammation, injury, and fibrosis, thus driving liver disease progression.
CI  - (c) 2014 by the American Association for the Study of Liver Diseases.
FAU - Shen, Hong
AU  - Shen H
AD  - Department of Molecular & Integrative Physiology, University of Michigan Medical 
      School, Ann Arbor, MI.
FAU - Sheng, Liang
AU  - Sheng L
FAU - Chen, Zheng
AU  - Chen Z
FAU - Jiang, Lin
AU  - Jiang L
FAU - Su, Haoran
AU  - Su H
FAU - Yin, Lei
AU  - Yin L
FAU - Omary, M Bishr
AU  - Omary MB
FAU - Rui, Liangyou
AU  - Rui L
LA  - eng
GR  - R01 DK091591/DK/NIDDK NIH HHS/United States
GR  - NIH DK34933/DK/NIDDK NIH HHS/United States
GR  - P30 CA046592/CA/NCI NIH HHS/United States
GR  - DK094014/DK/NIDDK NIH HHS/United States
GR  - NIH DK20572/DK/NIDDK NIH HHS/United States
GR  - DK091591/DK/NIDDK NIH HHS/United States
GR  - NIH CA46592/CA/NCI NIH HHS/United States
GR  - NIH P30AG013283/AG/NIA NIH HHS/United States
GR  - DK52951/DK/NIDDK NIH HHS/United States
GR  - R01 DK094014/DK/NIDDK NIH HHS/United States
GR  - P30 DK020572/DK/NIDDK NIH HHS/United States
GR  - P30 AG013283/AG/NIA NIH HHS/United States
GR  - P60 DK020572/DK/NIDDK NIH HHS/United States
GR  - P30 DK034933/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20141029
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
SB  - IM
MH  - Adult
MH  - Animals
MH  - Apoptosis
MH  - Female
MH  - Fibrosis
MH  - Hepatocytes/*physiology
MH  - Humans
MH  - Immunity, Innate
MH  - Liver/pathology
MH  - Liver Diseases/immunology/*metabolism/pathology
MH  - Macrophages/physiology
MH  - Male
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Middle Aged
MH  - Oxidative Stress
MH  - Protein Serine-Threonine Kinases/*metabolism
MH  - Young Adult
MH  - NF-kappaB-Inducing Kinase
PMC - PMC4245385
MID - NIHMS620333
EDAT- 2014/08/05 06:00
MHDA- 2015/02/12 06:00
PMCR- 2015/12/01
CRDT- 2014/08/05 06:00
PHST- 2014/03/07 00:00 [received]
PHST- 2014/07/28 00:00 [accepted]
PHST- 2014/08/05 06:00 [entrez]
PHST- 2014/08/05 06:00 [pubmed]
PHST- 2015/02/12 06:00 [medline]
PHST- 2015/12/01 00:00 [pmc-release]
AID - 10.1002/hep.27348 [doi]
PST - ppublish
SO  - Hepatology. 2014 Dec;60(6):2065-76. doi: 10.1002/hep.27348. Epub 2014 Oct 29.