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Splenectomy improves liver fibrosis via tumor necrosis factor superfamily 14 (LIGHT) through the JNK/TGF-β1 signaling pathway

Experimental & Molecular Medicine 2021년 53권 3호 p.393 ~ 406
Liang Qing-Shan, Xie Jian-Gang, Yu Chao Ping, Feng Zhu Sheng, Ma Jing Chang, Zhang Yuan, Wang Dong, Lu Jian Guo, Zhuang Ran, Yin Jikai,
소속 상세정보
 ( Liang Qing-Shan ) - Air Force Military Medical University Second Affiliated Hospital Department of General Surgery
 ( Xie Jian-Gang ) - Air Force Military Medical University First Affiliated Hospital Department of Emergency
 ( Yu Chao Ping ) - Air Force Military Medical University First Affiliated Hospital Department of Emergency
 ( Feng Zhu Sheng ) - Air Force Military Medical University First Affiliated Hospital Department of Emergency
 ( Ma Jing Chang ) - Air Force Military Medical University School of Basic Medical Sciences Department of Immunology
 ( Zhang Yuan ) - Air Force Military Medical University School of Basic Medical Sciences Transplant Immunology Laboratory
 ( Wang Dong ) - Air Force Military Medical University Second Affiliated Hospital Department of General Surgery
 ( Lu Jian Guo ) - Air Force Military Medical University Second Affiliated Hospital Department of General Surgery
 ( Zhuang Ran ) - Air Force Military Medical University School of Basic Medical Sciences Department of Immunology
 ( Yin Jikai ) - Air Force Military Medical University Second Affiliated Hospital Department of General Surgery

Abstract


Splenectomy has been reported to improve liver fibrosis in patients with cirrhosis and hypersplenism. However, the mechanisms remain unclear. Tumor necrosis factor superfamily 14 (TNFSF14; also known as LIGHT) is highly expressed in the context of fibrosis and promotes disease progression in patients with fibrotic diseases such as pulmonary and skin fibrosis. Here, we determined whether splenectomy controls the production of LIGHT to improve liver fibrosis. Splenectomy reduced serum LIGHT levels in cirrhotic patients with hypersplenism and a ConA-induced liver fibrosis mouse model. Blocking LIGHT resulted in the downregulation of TGF-β1 in RAW264.7 cells. LIGHT treatment of RAW264.7 and JS1 cells in coculture regulated transforming growth factor-β1 (TGF-β1) expression through the activation of JNK signaling. Small interfering RNA-mediated silencing of lymphotoxin β receptor (LTβR) in macrophages resulted in pronounced decreases in the levels of fibrosis and αSMA in JS1 cells. These results indicated that LIGHT bound to LTβR and drove liver fibrosis in vitro. Blocking TGF-β1 abolished the effect of LIGHT in vitro. Furthermore, the administration of recombinant murine LIGHT protein-induced liver fibrosis with splenectomy, while blocking LIGHT without splenectomy improved liver fibrosis in vivo, revealing that the decrease in fibrosis following splenectomy was directly related to reduced levels of LIGHT. Thus, high levels of LIGHT derived from the spleen and hepatic macrophages activate JNK signaling and lead to increased TGF-β1 production in hepatic macrophages. Splenectomy attenuates liver fibrosis by decreasing the expression of LIGHT.

키워드

Experimental models of disease; Hepatic stellate cells; Liver cirrhosis; Liver fibrosis; Tumour-necrosis factors

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