Methylprednisolone Decreases Mitochondria-Mediated Apoptosis and Autophagy Dysfunction in Hepatocytes of Experimental Autoimmune Hepatitis Model via the Akt/mTOR Signaling

Abstract

Autoimmune hepatitis (AIH) is characterized by massive immune cell-mediated hepatocyte destruction. Glucocorticoids, particularly methylprednisolone (MP), are the most effective treatment for AIH; however, the mechanism underlying the effects of glucocorticoid treatment has not been fully elucidated. The present study explored the effects of MP on damaged hepatocytes in mice with concanavalin A (ConA)−induced experimental autoimmune hepatitis (EAH). C57BL/6 mice were divided into three groups: a normal control group (injected with normal saline), a ConA (20 mg/kg) group, and a ConA + MP (3.12 mg/kg) group. The serum levels of liver enzymes, cytokines, activated T cells, and apoptosis− and autophagy−associated marker proteins were determined 12 h after ConA injection. Human hepatocyte cell line LO2 was used to verify the effects of ConA and MP in vitro. MP treatment significantly decreased inflammatory reactions in the serum and liver tissues and activated the Akt/mTOR signaling pathway to inhibit apoptosis and autophagy in hepatocytes in vivo. Transmission electron microscopy (TEM) revealed fewer autophagosomes in the MP-treated group than in the ConA-treated group. MP treatment obviously suppressed apoptosis and mitochondrial membrane potential (ΔΨm) loss in hepatocytes in vitro. Furthermore, ConA treatment increased the levels of LC3-II, p62/SQSTM1, and Beclin-1, while bafilomycin A1 did not augment the levels of LC3-II. MP treatment decreased the levels of LC3-II, p62/SQSTM1, and Beclin-1 and upregulated the levels of phosphorylated (p)-Akt and p-mTOR. In conclusion, MP ameliorated mitochondria-mediated apoptosis and autophagy dysfunction in ConA-induced hepatocyte injury in vivo and in vitro via the Akt/mTOR signaling pathway.

Critical roles of conventional dendritic cells in autoimmune hepatitis via autophagy regulation

“…The EAH model was established at 12 h after an injection of ConA with a dose of 20 mg/kg through the tail vein, which was based on our previous study and other reported articles [11][12][13][14] . To evaluate the EAH model, the mice were divided into two groups: (1) Mice were given a single intravenous injection of normal saline as a vehicle control.…”

“…To investigate the role of cDCs in the pathogenesis of EAH, we developed a mouse model of ConA-induced AIH as in our previous study 11,14,19 . As shown by liver function and H&E, EAH was successfully established after ConA injection in EAH model ( Supplementary Fig.…”

Circular RNAs associated with a mouse model of concanavalin A‐induced autoimmune hepatitis: preliminary screening and comprehensive functional analysis

“…Furthermore, it was evident that mTOR may affect diverse processes in T cells by coordinately regulating immune receptor signaling pathways, metabolic programs and migratory activity [45]. It has been reported that the mitochondria‐mediated apoptosis and autophagy dysfunction in Con A‐induced hepatocyte injury in vivo and in vitro were connected with the Akt/mTOR signaling pathway [46]. Apoptosis is considered as a crucial component of various processes, including development of the immune system, and inappropriate apoptosis (either too little or too much) is a vital factor in the generation of AIH.…”

Autophagy in liver diseases

“…Reduced numbers of autophagosomes were present in the MP treated group compared to the conA group. It was further shown that MP attenuated the mitochondria-mediated autophagy and apoptosis[ 655 ]. In a second report on the same experimental model, accumulation of mature conventional dendritic cells (cDCs) was observed in the liver.…”