期刊
HEPATOLOGY
卷 47, 期 1, 页码 199-206出版社
WILEY
DOI: 10.1002/hep.21970
关键词
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资金
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R56AI023847, R01AI042223, R01AI023847, R21AI023847] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK062357] Funding Source: NIH RePORTER
- NIAID NIH HHS [AI42223, AI23847] Funding Source: Medline
- NIDDK NIH HHS [R01 DK062357] Funding Source: Medline
We have documented the key role of toll-like receptor 4 (TLR4) activation and its signaling pathway mediated by interferon (IFN) regulatory factor 3, in the induction of inflammation leading to the hepatocellular damage during liver ischemia/reperfusion injury (IRI). Because type I IFN is the major downstream activation product of that pathway, we studied its role in comparison with IFN-gamma. Groups of type I (IFNAR), type II (IFNGR) IFN receptor-deficient mice, along with wild-type (WT) controls were subjected to partial liver warm ischemia (90 minutes) followed by reperfusion (1-6 hours). Interestingly, IFNAR knockout (KO) but not IFNGR KO mice were protected from IR-induced liver damage, as evidenced by decreased serum alanine aminotransferase and preservation of tissue architecture. IR-triggered intrahepatic pro-inflammatory response, assessed by tumor necrosis factor (TNF-alpha), interleukin 6 (IL-6), and chemokine (C-X-C motif) ligand 10 (CXCL-10) expression, was diminished selectively in IFNAR KO mice. Consistent with these findings, our in vitro cell culture studies have shown that: (1) although hepatocytes alone failed to respond to lipopolysaccharide (LPS), when co-cultured with macrophages they did respond to LPS via macrophage-derived IFN-beta; (2) macrophages required type I IFN to sustain CXCL10 production in response to LPS. This study documents that type I, but not type II, IFN pathway is required for IR-triggered liver inflammation/damage. Type I IFN mediates potential synergy between nonparenchyma and parenchyma cells in response to TLR4 activation.
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