title: Mouse hepatocyte overexpression of NF-κB-inducing kinase (NIK) triggers fatal macrophage-dependent liver injury and fibrosis.
abstract: 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-κB)-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.
  
  
  CONCLUSIONS
  the hepatocyte NIK-liver immune cell axis promotes liver inflammation, injury, and fibrosis, thus driving liver disease progression.
authors.affiliation: Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI.
authors.forename: Hong
authors.initials: H
authors.lastname: Shen
authors.forename: Liang
authors.initials: L
authors.lastname: Sheng
authors.forename: Zheng
authors.initials: Z
authors.lastname: Chen
authors.forename: Lin
authors.initials: L
authors.lastname: Jiang
authors.forename: Haoran
authors.initials: H
authors.lastname: Su
authors.forename: Lei
authors.initials: L
authors.lastname: Yin
authors.forename: M Bishr
authors.initials: MB
authors.lastname: Omary
authors.forename: Liangyou
authors.initials: L
authors.lastname: Rui
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis; D005260:Female; D005355:Fibrosis; D022781:Hepatocytes / Q000502:physiology*; D006801:Humans; D007113:Immunity, Innate; D008099:Liver / Q000473:pathology; D008107:Liver Diseases / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000502:physiology; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D018384:Oxidative Stress; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D055815:Young Adult; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D017346:Protein Serine-Threonine Kinases; D000097782:NF-kappaB-Inducing Kinase
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