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Toll‐like receptor 7‐mediated type I interferon signaling prevents cholestasis‐ and hepatotoxin‐induced liver fibrosis
Author(s) -
Roh Yoon Seok,
Park Surim,
Kim Jong Won,
Lim Chae Woong,
Seki Ekihiro,
Kim Bumseok
Publication year - 2014
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.26981
Subject(s) - hepatotoxin , cholestasis , interferon , toll like receptor , fibrosis , liver fibrosis , medicine , receptor , immunology , innate immune system , toxicity
Toll‐like receptor 7 (TLR7) signaling predominantly regulates production of type I interferons (IFNs), which has been suggested in clinical studies to be antifibrotic. However, the mechanistic role of the TLR7‐type I IFN axis in liver fibrosis has not been elucidated. In the present study, liver fibrosis was induced in wild‐type (WT), TLR7‐deficient, and IFN‐α/β receptor‐1 (IFNAR1)‐deficient mice and TLR7‐mediated signaling was assessed in liver cells isolated from these mice. TLR7‐deficient and IFNAR1‐deficient mice were more susceptible to liver fibrosis than WT mice, indicating that TLR7‐type I IFN signaling exerts a protective effect against liver fibrosis. Notably, the hepatic expression of interleukin‐1 receptor antagonist (IL‐1ra) was suppressed in TLR7‐ or IFNAR1‐deficient mice compared with respective WT mice, and treatment with recombinant IL‐1ra reduced liver fibrosis. In vivo activation of TLR7 significantly increased IFNa4 and IL‐1ra expression in the liver. Interestingly, each cytokine had a different cellular source, showing that dendritic cells (DCs) are the responsible cell type for production of type I IFN, while Kupffer cells (KCs) mainly produce IL‐1ra in response to type I IFN. Furthermore, TLR7 activation by R848 injection suppressed liver fibrosis and production of proinflammatory cytokines, and these effects were dependent on type I IFN signaling. Consistent with in vivo data, IFN‐α significantly induced IL‐1ra production in primary KCs. Conclusion : TLR7 signaling activates DCs to produce type I IFN, which in turn induces antifibrogenic IL‐1ra production in KCs. Thus, manipulation of the TLR7‐type I IFN‐IL‐1ra axis may be a new therapeutic strategy for the treatment of liver fibrosis. (H epatology 2014;60:237–249)

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