Open AccessCXCL 6‐ EGFR ‐induced Kupffer cells secrete TGF ‐β1 promoting hepatic stellate cell activation via the SMAD 2/ BRD 4/C‐ MYC / EZH 2 pathway in liver fibrosis
Author(s) -
Cai Xiaobo,
Li Zhenghong,
Zhang Qidi,
Qu Yin,
Xu Mingyi,
Wan Xinjian,
Lu Lungen
Publication year - 2018
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.13787
Subject(s) - smad , hepatic stellate cell , chemokine , fibrosis , secretion , transforming growth factor , cancer research , kupffer cell , chemistry , biology , microbiology and biotechnology , immunology , inflammation , medicine , endocrinology
Liver fibrosis is the excessive accumulation of extracellular matrix proteins in response to the inflammatory response that accompanies tissue injury, which at an advanced stage can lead to cirrhosis and even liver failure. This study investigated the role of the CXC chemokine CXCL 6 ( GCP ‐2) in liver fibrosis. The expression of CXCL 6 was found to be elevated in the serum and liver tissue of high stage liver fibrosis patients. Furthermore, treatment with CXCL 6 (100 ng/mL) stimulated the phosphorylation of EGFR and the expression of TGF ‐β in cultured Kupffer cells ( KC s). Although treatment with CXCL 6 directly did not activate the hepatic stellate cell ( HSC ) line, HSC ‐T6, HSC s cultured with media taken from KC s treated with CXCL 6 or TGF ‐β showed increased expression of α‐ SMA , a marker of HSC activation. CXCL 6 was shown to function via the SMAD 2/ BRD 4/C‐ MYC / EZH 2 pathway by enhancing the SMAD 3‐ BRD 4 interaction and promoting direct binding of BRD 4 to the C‐ MYC promoter and CMY ‐C to the EZH 2 promoter, thereby inducing profibrogenic gene expression in HSC s, leading to activation and transdifferentiation into fibrogenic myofibroblasts. These findings were confirmed in a mouse model of CC l 4 ‐induced chronic liver injury and fibrosis in which the levels of CXCL 6 and TGF ‐β in serum and the expression of α‐ SMA , SMAD 3, BRD 4, C‐ MYC , and EZH 2 in liver tissue were increased. Taken together, our results reveal that CXCL 6 plays an important role in liver fibrosis through stimulating the release of TGF ‐β by KC s and thereby activating HSC s.