concanavalin-a and taxifolin

We have previously demonstrated the hepatoprotective effect of dihydroquercetin (DHQ) against concanavalin A (Con A)-induced immunological hepatic injury in mice. In this study, we investigated the immunoregulatory effects of DHQ on Con A-induced liver injury in mice. DHQ administration significantly decreased the serum levels of alanine transaminase and aspartate transaminase, effectively prevented liver damage, and increased the survival rate of Con A-treated mice. Immunohistochemistry examination revealed that supplementation with DHQ obviously reduced infiltration of CD4+ and CD8+ T cells in the injured liver tissues. Furthermore, DHQ administration resulted in down-regulation of pro-inflammatory cytokines (TNF-α, IFN-γ, IL-2, IL-4, and IL-10), the chemokine osteopontin, apoptosis factors (Fas and FasL), transcription factors that regulate Th cell differentiation (T-bet and GATA-3), perforin, granzyme B, and inducible nitric oxide synthase (iNOS). In vitro, treatment with DHQ protected HepG2 cells against TNF-α/ActD-induced apoptosis by inhibiting the activation of caspase-3, caspase-7, and caspase-8. In addition, DHQ reduced phosphorylation of NF-kB/p65, and inhibited the expressions of pro-apoptotic factors (p53 and Bax), while it up-regulated the expression of the anti-apoptotic factor Bcl-2. Our findings suggest that the immunosuppressive effects of DHQ ameliorated Con A-mediated immunological liver injury by reducing the expression of pro-inflammatory mediators and infiltration of CD4+ and CD8+ T cells in liver tissues, and DHQ protected HepG2 cells against TNF-α/ActD-induced apoptosis possibly via modulation of the caspase and NF-kB pathways.

Topics: Animals; Apoptosis; Chemical and Drug Induced Liver Injury; Concanavalin A; Hep G2 Cells; Humans; Interleukin-10; Interleukin-2; Liver; Male; Mice; Mice, Inbred BALB C; Nitric Oxide Synthase Type II; Quercetin; Tumor Necrosis Factor-alpha

Autoimmune hepatitis represents a ubiquitous human health problem and has a poor prognosis. Dihydroquercetin (DHQ), a well-known antioxidant, significantly inhibits fulminant hepatitis through anti-oxidant and anti-inflammation mechanisms. In this study, we show that administration of DHQ ameliorated concanavalin A (ConA)-induced mouse liver injury by increasing the survival rate, reducing the serum ALT and AST level, preventing histopathological injuries and decreasing pro-inflammatory cytokine mRNA expression in hepatic tissue. As macrophages/Kupffer cells in oxidative stress and pro-inflammatory mediators play an important role in the pathogenesis of immune-mediated hepatitis, we further exposed mouse RAW264 macrophage cell lines to ConA in vitro and found that DHQ significantly inhibited mRNA expression and secretion of IFN-γ and TNF-α in cell culture supernatant. In addition, DHQ significantly enhanced heme oxygenase-1 (HO-1) expression in a dose- and time-dependent manner via increased Nrf2 expression in cytoplasm and nuclear translocation. Furthermore, DHQ enhanced phosphorylation of three members of the mitogen-activated protein kinase (MAPK) family, and cell treatment with MEK/ERK (PD98059), p38 (SB203580) and JNK (SP600125) inhibitors reduced DHQ-induced HO-1 expression. These results indicate that DHQ possesses hepatoprotective properties against ConA-induced liver injury, which are attributed to its ability to scavenge oxidative stress and to inhibit the release of inflammatory mediators via upregulation of HO-1 activity through the MAPK/Nrf2 signaling pathway in macrophages/Kupffer cells.

Topics: Animals; Antioxidants; Autoimmune Diseases; Cell Line; Concanavalin A; Extracellular Signal-Regulated MAP Kinases; Heme Oxygenase-1; Hepatitis; Humans; Immunity; Interferon-gamma; Macrophages; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Models, Animal; NF-E2-Related Factor 2; Quercetin; Signal Transduction; Tumor Necrosis Factor-alpha