Qing-Yi Cao1, Feng Chen, Jie Li, Shan-Shan Wu, Jing Wang, Zhi Chen. 1. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.
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(R) 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 receptor-intermediated apoptosis, resulting in liver injury.
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(R) 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 receptor-intermediated apoptosis, resulting in liver injury.
Authors: M Ashburner; C A Ball; J A Blake; D Botstein; H Butler; J M Cherry; A P Davis; K Dolinski; S S Dwight; J T Eppig; M A Harris; D P Hill; L Issel-Tarver; A Kasarskis; S Lewis; J C Matese; J E Richardson; M Ringwald; G M Rubin; G Sherlock Journal: Nat Genet Date: 2000-05 Impact factor: 38.330
Authors: Rafael A Irizarry; Benjamin M Bolstad; Francois Collin; Leslie M Cope; Bridget Hobbs; Terence P Speed Journal: Nucleic Acids Res Date: 2003-02-15 Impact factor: 16.971
Authors: Y Kaneko; M Harada; T Kawano; M Yamashita; Y Shibata; F Gejyo; T Nakayama; M Taniguchi Journal: J Exp Med Date: 2000-01-03 Impact factor: 14.307