期刊
HEPATOLOGY
卷 60, 期 6, 页码 2065-2076出版社
WILEY-BLACKWELL
DOI: 10.1002/hep.27348
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资金
- NCI NIH HHS [P30 CA046592, NIH CA46592] Funding Source: Medline
- NIA NIH HHS [P30 AG013283, NIH P30AG013283] Funding Source: Medline
- NIDDK NIH HHS [R01 DK091591, DK52951, P60 DK020572, DK094014, NIH DK34933, DK091591, P30 DK020572, P30 DK034933, R01 DK094014, NIH DK20572] Funding Source: Medline
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-kappa B)-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 marrowderived 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.
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