Abstract
Purpose To investigate the roles of ER stress in Kupffer cells (KCs) and KC-derived TNF-α in the apoptosis of hepatic stellate cells (HSCs). Methods A rat model of liver fibrosis was established. Liver and blood serum samples were collected. Liver function assays, Masson staining, Sirius Red staining, ELISAs, and TUNEL and immunohistochemical staining were performed. Liver function, liver fibrosis, KC phenotype, inflammatory factors, and number of active HSCs were investigated. KCs were isolated, treated with tunicamycin, and then, cocultured with primary hepatic stellate cells. ELISAs, immunofluorescence staining, flow cytometry, and Western blotting were performed. KC phenotype, inflammatory factors, HSC apoptosis, and TNF-R1/caspase 8 pathway activity were examined. Results. ER stress in KCs reduced the levels of liver function markers, reduced the degree of liver fibrosis, and increased the number of KCs with the M1 phenotype and the expression of TNF-α. The increase in KC-derived TNF-α reduced the number of active HSCs and increased the activity of TNF-R1/caspase 8. Furthermore, ER stress in KCs promoted the polarization of KCs towards the M1 phenotype and increased the expression of TNF-α. The increase in KC-derived TNF-α triggered the apoptosis of HSCs and the activation of TNF-R1/caspase 8 in vitro, which was consistent with the in vivo results. Conclusion ER stress in KCs promotes the polarization of these cells towards the M1 phenotype and increases the expression of TNF-α. Then, the increase in KC-derived TNF-α triggers the apoptosis of HSCs through TNF-R1/caspase 8.
Highlights
Hepatic fibrosis is a self-healing process caused by multiple chronic liver injuries
Panebianco et al [3] reviewed the role of retinoic acid signaling in modulating the fibrogenic potential of hepatic stellate cells (HSCs) and proposed that it acts in synergy with PPAR-γ in the reversal of liver fibrosis
TNF-α is widely believed to be involved in the regulation of apoptosis in multiple cell types [13,14,15], but whether ER stress-induced TNF-α secretion by Kupffer cells (KCs) has an effect on the apoptosis of active HSCs has not been reported
Summary
Hepatic fibrosis is a self-healing process caused by multiple chronic liver injuries. Hepatic fibrosis is characterized by the deposition of large amounts of extracellular matrix, which leads to the abnormal proliferation of connective tissue in the liver [1] In this pathological progression, liver fibrosis is the only reversible process. Many previous studies have shown that active HSCs play an important role in the progression of hepatic fibrosis. Previous studies have shown that ER stress plays an important regulatory role in inducing the apoptosis of active HSCs. Wang et al [5] postulated that etoposide induces apoptosis in activated human HSCs via ER stress. TNF-α is widely believed to be involved in the regulation of apoptosis in multiple cell types [13,14,15], but whether ER stress-induced TNF-α secretion by KCs has an effect on the apoptosis of active HSCs has not been reported. HSCs, as well as the possible underlying mechanism, and aimed to identify new treatments to reverse the progression of hepatic fibrosis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
