title: Substance P participates in immune-mediated hepatic injury induced by concanavalin A in mice and stimulates cytokine synthesis in Kupffer cells.
abstract: Studies have indicated that the immune system plays a pivotal role in hepatitis. Substance P (SP) has been shown to modulate the immune response. In order to investigate the role of SP in liver injury and to determine whether it leads to pro-inflammatory signaling, we established a mouse model of hepatic injury induced by concanavalin A (ConA). We also exposed mouse Kupffer cells (KCs) to SPin vitro. Cytokine and SP levels in liver homogenates were detected using enzyme-linked immunosorbent assay (ELISA) and the protective effects of L-703,606 were evaluated through serological and histological assessments. Neurokinin-1 receptor (NK-1R) expression was evaluated by immunofluorescence and quantitative polymerase chain reaction (PCR). The levels of SP, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were significantly increased in the ConA-treated mice and the levels of ALT and AST were markedly reduced by L-703,606-pretreatment. Liver injury was significantly reduced by treatment with L-703,606. The mouse KCs expressed NK-1R and SP increased NK-1R mRNA expression. Furthermore, NK-1R blockade eliminated the effect of SP on NK-1R mRNA expression. The cytokine levels exhibited a substantial increase in the SP-pretreated KCs compared with the KCs that were cultured in control medium. The inter-leukin (IL)-6 and tumor necrosis factor (TNF)-α levels in the L-703,606-pretreated KCs were significantly lower compared with those in the SP-pretreated KCs. Our study suggests that neurogenic inflammation induced by SP plays an important role in hepatitis. Mouse KCs express NK-1R and SP increases NK-1R mRNA expression. SP enhances IL-6 and TNF-α secretion and an NK-1R antagonist inhibits this secretion.
authors.affiliation: Health Examination Center, Qilu Hospital of Shandong University, Jinan, Shandong 250012;
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.forename: Ming
authors.initials: M
authors.lastname: Yan
authors.forename: Haitao
authors.initials: H
authors.lastname: Zhang
authors.forename: Xuping
authors.initials: X
authors.lastname: Wang
keywords: concanavalin A; liver injury; neurogenic inflammation; neurokinin 1 receptor antagonist; substance P