Protective Effect of Ellagic Acid on Concanavalin A‑Induced Hepatitis via Toll-Like Receptor and Mitogen-Activated Protein Kinase/Nuclear Factor κB Signaling Pathways

Ellagic acid (EA) is present in certain fruits and nuts, including raspberries, pomegranates, and walnuts, and has anti-inflammatory and antioxidant properties. The aims of this study were to examine the protective effect of EA on concanavalin A (Con A)-induced hepatitis and to elucidate its underlying molecular mechanisms in mice. Mice were orally administered EA at different doses before the intravenous delivery of Con A; the different experimental groups were as follows: (i) vehicle control, (ii) Con A alone without EA, (iii) EA at 50 mg/kg, (iv) EA at 100 mg/kg, and (v) EA at 200 mg/kg. We found that EA pretreatment significantly reduced the levels of plasma aminotransferase and liver necrosis in Con A-induced hepatitis. Also, EA significantly decreased the expression levels of the toll-like receptor 2 (TLR2) and TLR4 mRNA and protein in liver tissues. Further, EA decreased the phosphorylation of JNK, ERK1/2, and p38. EA-treated groups showed suppressions of nuclear factor κB (NF-κB) and IκB-α degradation levels in liver tissues. In addition, EA pretreatment decreased the expression of pro-inflammatory cytokines, such as tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and interleukin 1β (IL-1β). These results suggest that EA protects against T-cell-mediated hepatitis through TLR and mitogen-activated protein kinase (MAPK)/NF-κB signaling pathways.