A microarray analysis of early activated pathways in concanavalin A-induced hepatitis

Abstract

Abstract:Objective: To explore the mechanisms of fulminant hepatitis (FH) in the early stages, and to determine the critical pathways in its initiation and progression. Methods: Twelve BALB/c mice were divided into four groups: one group left as negative control and sacrificed immediately after injection of phosphate-buffered saline (PBS), and another three groups with concanavalin A (Con A) administration sacrificed at 1, 3, and 6 h after injection. Affymetrix GeneChip® Mouse 430 2.0 Array was employed to evaluate the expression profile of each of the 12 samples. Further analysis was done on the microarray data to extract the genes that were differentially expressed. Enrichment analysis was carried out to determine relevant pathways within which regulated genes were significantly enriched. Results: A total of 393, 8354 and 11 344 differentially expressed genes were found, respectively, at three time points. During 0-1 h and 1-3 h, most of the pathways enriched with regulated genes were related to immune response and inflammation, among which Toll-like receptor (TLR) signaling and mitogen-activated protein kinase (MAPK) signaling appeared during both phases, while cytokine-cytokine receptor interaction, apoptosis, T cell receptor signaling, and natural killer (NK) cell-mediated cytotoxicity pathways emerged during the second phase. Pathways found to be significant during 3-6 h were mostly related to metabolic processes. Conclusion: The TLR signaling pathway dominates the early responses of Con A-induced FH in mice. It stimulates the production of type I cytokines, therefore recruiting and activating T/NK cells. Activated T/NK cells exert their cytotoxicity on hepatocytes through inducing death receptorintermediated apoptosis, resulting in liver injury.

Involvement of REST corepressor 3 in prognosis of human hepatitis B

“…The extent of liver injury was also evaluated by determining serum ALT, AST, STB, and LDH using the standard Reitman-Frankel method. The results can be seen in our previous articles [16,17] .…”

“…Ji-hua XUE, Min ZHENG, Xiao-wei XU, Shan-shan WU, Zhi CHEN, Feng CHEN * npg In a previous study, we obtained the gene expression profile of livers from mice in a concanavalin A (ConA)-induced hepatitis model by GeneChip array [16,17] . ConA-induced hepatic injury in mice has long been established as a model of immunologically induced hepatocyte injury because its histological features highly resemble those of viral or druginduced acute hepatitis in humans [18] .…”

Curcumin attenuates Concanavalin A-induced liver injury in mice by inhibition of Toll-like receptor (TLR) 2, TLR4 and TLR9 expression

“…In the liver, TLRs are widely expressed on Kupffer cells, hepatocytes, hepatic stellate cells, biliary epithelial cells, sinusoidal endothelial cells, and hepatic dendritic cells [9][10][11][12][13][14][15], which play critical roles for the liver health [9,10]. Also, the liver is constantly exposed to gut-derived bacterial products, suggesting that bacterial products and TLRs might be involved in liver diseases.…”

“…Indeed, recent studies indicated that TLRmedicated signals have been involved in almost all liver diseases [7][8][9][10][11][12][13][14][15]. Recent studies implicating TLR2, TLR4 and TLR9 signaling in Con A-induced liver injury are also of particular [10][11][12][13][14][15]. Ojiro K et al [11] found that the TLRs-MyD88 signaling pathway in liver macrophages was critically involved in the pathogenesis of Con A-induced liver damage.…”

“…Ojiro K et al [11] found that the TLRs-MyD88 signaling pathway in liver macrophages was critically involved in the pathogenesis of Con A-induced liver damage. Also, the expression of TLR2, TLR4 and TLR9 was upregulated in liver cells during Con A-induced [11][12][13]. Furthermore, mice deficient for TLR2 or TLR4 were protected from Con A-induced hepatic injury as compared with wild-type mice [12,15].…”