The purpose of this study was to investigate whether pituitary adenylate cyclase-activating polypeptide (PACAP) prevents mortality due to sepsis in mice. Mice were given PACAP at designated time points before or after cecal ligation and puncture (CLP), and organ injury and mortality were investigated. Serum inflammatory and anti-inflammatory cytokine levels were assessed after CLP. Plasma corticosterone and adrenocorticotropic hormone levels were also measured. Isolated tissue macrophages (Mfs) were incubated with or without PACAP, and production of cytokines was measured. Activation of NF-κB was investigated in tissue Mfs isolated from CLP animal in the presence and absence PACAP in vitro. PACAP treatment significantly prevented acute lung injury and mortality after CLP. Plasma endotoxin levels and bacterial load were not different between PACAP-treated and nontreated groups. Increased serum TNF-α and HMGB1 levels in animals treated with vehicle were significantly blunted in PACAP-treated animals after CLP. Furthermore, serum IL-10 levels were significantly greater in the PACAP-treated group compared with the vehicle group. Production of HMGB1 and TNF-α by isolated hepatic Mfs was significantly inhibited in the presence of PACAP, whereas production of IL-10 by isolated hepatic Mfs and interstitial lung Mfs was significantly increased. Plasma corticosterone and adrenocorticotropic hormone levels were significantly greater in the animals treated with PACAP compared with vehicle after CLP. Activation of NF-κB was significantly inhibited by PACAP in the hepatic Mfs compared with other tissue Mfs. PACAP prevents mortality due to septic peritonitis by inhibiting inflammation via NF-κB activation and possible effects on the brain.

Background/Aim: The aim of this study was to investigate the effects of the macrophage colony-stimulating factor (M-CSF) receptor antagonist on hepatic carcinogenesis in mice. Materials and Methods: Mice were injected with diethylnitrosamine (DEN) and treated with M-CSF receptor antagonist GW2580 (GW) or a saline vehicle just after (early treated group) or 2 weeks after (late treated group) DEN injection. Animals were sacrificed after 28 weeks and incidence of tumor was assessed. Isolated Kupffer cells were co-cultured with M-CSF in the presence or absence of GW, and the concentration of VEGF was measured. Results: The incidence of tumors was significantly blunted both in the early- and the late-treated groups. In addition, angiogenesis within the tumor was also suppressed in both groups. The concentration of VEGF increased in Kupffer cells treated with M-CSF compared to those cultured without M-CSF. This increase was blunted by GW. Conclusion: M-CSF and its receptor could be novel molecular targets for hepatocellular carcinoma.

Background: Lipopolysaccharide/D-galactosamine (LPS/GalN)-induced hepatic injury is an experimental model of fulminant hepatic failure in which tumor necrosis factor alpha (TNF-alpha) plays a pivotal role. Moreover, it was reported from our laboratory that interleukin (IL) 17A enhanced production of TNF-alpha by the Kupffer cell.Objective: The purpose of this study was to determine the role of IL-17A in LPS/GalN-induced hepatic injury in mice.Methods: LPS/GalN was injected into three mouse models: wild-type (WT) mice, IL-17A knockout (KO) mice, or IL-17A KO mice treated with recombinant mouse (rm) IL-17A homodimer (KO + rmIL-17A). Survival was assessed for 24 h after LPS/GalN injection, and histopathologic findings were evaluated at various time points after LPS/GalN injection for neutrophil and apoptosis markers. After LPS/GalN injection, expression of the inflammatory mediators TNF-alpha, IL-6, monocyte chemotactic protein 1, IL-17A, high-mobility group box 1, and soluble intercellular adhesion molecule 1 was assessed in serum by enzyme-linked immunosorbent assay.Results: Survival was higher in KO mice compared with WT mice after LPS/GalN injection. However, in KO + rmIL-17A mice, mortality was not significantly different compared to the other groups. Neutrophil infiltration and apoptosis were significantly greater in WT mice than KO mice. Furthermore, serum alanine aminotransferase, serum TNF-alpha, monocyte chemotactic protein 1, IL-17A, high-mobility group box 1, and soluble intercellular adhesion molecule 1 levels were also significantly greater in WT mice than KO mice. In KO + rmIL-17A mice, these levels were similar to those in WT mice.Conclusions: IL-17A is a key regulator in hepatic injury caused by neutrophil-induced inflammatory responses after LPS/GalN injection. (C) 2015 The Authors. Published by Elsevier Inc.

Aim The aim of the present study was to investigate the role of interleukin (IL)-17A in the initiation and progression of hepatocellular carcinoma. Methods IL-17A deficient (KO) and wild-type (WT) mice were intraperitoneal injected with diethyl nitrosamine (DEN) to induce hepatocellular carcinoma, and the incidence of tumours was assessed 38 weeks later. In order to investigate the effects of DEN on hepatocytes in the acute phase of DEN administration, DEN-treated mice were sacrificed at designated time points. Serum and liver tissues were harvested for further analyses. Results The tumor incidence was approximately 65 % in WT mice, but was significantly lower (by 20 %) in KO mice. The number of tumours was also less in KO mice. Serum ALT levels increased in WT mice 7 days after the administration of DEN, but were significantly lower in KO mice. Furthermore, the number of neutrophils and Kupffer cells, and the expression of TNF-α and IL-6 were reduced in KO mice. The intrahepatic expression of the oxidative DNA damage marker 8-OHdG and lipid oxidative marker 4-HNE was markedly increased in WT mice, but was significantly lower in KO mice. In addition, the increase of cell proliferation, as assessed by Ki-67 immunohistochemistry, in WT mice was significantly reduced in KO mice. Conclusion These results demonstrated that IL-17A plays a pivotal role in chemically induced hepatic carcinogenesis, which is most likely through inflammation-initiated oxidative DNA damage and cell proliferation.