TGF‑β1‑induced autophagy activates hepatic stellate cells via the ERK and JNK signaling pathways

Abstract

Transforming growth factor β1 (TGF-β1) is one of the most important fibrogenic factors promoting the activation of hepatic stellate cells (HScs). Autophagy is a process used by cells to degrade and recycle cellular proteins. Although TGF-β1 induces autophagy in several other cellular systems, the association between its effect on fibrogenesis and autophagy in HScs have not been determined. Liver tissues from c57BL/6 mice and the mouse HSc line JS1 were analyzed. Acute and chronic liver injury models were induced by carbon tetrachloride (ccl 4), and JS1 cells were stimulated by TGF-β1 to assess the mechanism and relationship between autophagy and fibrosis. Liver tissues from acute and chronic injury models induced by ccl 4 demonstrated evidence of increased autophagic activity, as assessed by the expression of the microtubule-associated protein 1 light chain 3BII protein. TGF-β1 stimulated the activation of JS1 cells and simultaneously increased autophagy flux. However, this effect was attenuated when autophagy was inhibited using chloroquine, 3-methyladenine or lentiviral short hairpin RNA-mediated knockdown of autophagy-related gene 7. Furthermore, whether MAPK, including ERK, JNK and p38 MAPK cascades were associated with TGF-β1-induced autophagy in JS1 cells was determined. Subsequently, it was shown that the ERK inhibitor, Pd98059, and JNK inhibitor, SP600125, were able to reverse TGF-β1-induced autophagy and fibrosis. The results of the present study suggest that TGF-β1-induced autophagy is involved in the activation of JS1 cells, possibly through activation of the ERK and JNK signaling pathways.

HBV induces liver fibrosis via the TGF‑β1/miR‑21‑5p pathway

“…TGF-β1 was reported to be the key cytokine in the process of HSC activation and liver fibrosis ( 17 ). The present study investigated the role of miR-21-5p in TGF-β1-induced liver fibrosis.…”

“…In physiological conditions, quiescent-like HSCs exhibit necessary effects on lipid metabolism, maintaining the balance of extracellular matrix (ECM) production and degradation ( 16 ). When liver injury occurs, HSCs are activated by cytokines including TGF-β1 secreted by a variety of cells in the liver ( 17 ). These activated HSCs produce excessive ECM deposited in liver tissue disrupting liver structure leading to liver fibrogenesis ( 17 ).…”

“…When liver injury occurs, HSCs are activated by cytokines including TGF-β1 secreted by a variety of cells in the liver ( 17 ). These activated HSCs produce excessive ECM deposited in liver tissue disrupting liver structure leading to liver fibrogenesis ( 17 ).…”

The TGF-β/NADPH Oxidases Axis in the Regulation of Liver Cell Biology in Health and Disease

“…TGF-β-mediated ROS production, in a NOX4-dependent pathway, induces autophagy in epithelial cells [136]. During liver fibrosis, TGF-β1 induces autophagy through activation of the ERK and JNK signaling pathways [137], which play essential roles in regulating autophagic processes [138], and autophagy is involved in the activation of HSCs [137]. In fact, using cell culture and/or different animal models, numerous studies have shown that autophagy is enhanced during the fibrogenic process and have provided specific evidence to pinpoint the fundamental role of autophagy in HSCs activation [139].…”

A20 Attenuates Lipopolysaccharide-Induced Inflammation Through MAPK/ERK/JNK Pathway in LX-2 Cells

“…We previously found that LX-2 cells mount an inflammatory response and upregulate fibrosis indicators in response to LPS. Here, we focused on the MAPK/ERK/JNK signaling, which controls various processes in HSCs (20)(21)(22). Western blot analysis revealed elevated phosphorylated JNK and phosphorylated ERK levels in LX-2 cells relative to control (Figure 2).…”