7A). As described elsewhere,[15,

16, 25] ConA-driven hepatitis was accompanied by up-regulation of interferon-gamma (IFN-γ) and IL-17A RNA transcripts and protein (Supporting Fig. 7). Pretreatment of mice with IL-25 significantly reduced serum levels of both transaminases (Fig. 7A), attenuated histological damage (Fig. 7B), and decreased RNA and protein expression of IFN-γ and IL-17A (Supporting Fig. 7). Induction of liver damage by ConA was associated with infiltration of the liver by GR1+ and CD11b+ cells, and the presence of both these cell types was further increased in hepatitic mice treated with IL-25 (Fig. 7C). FCM analysis revealed that the percentage of GR1/CD11b+ double positive cells was higher in IL-25/ConA-treated mice, compared to mice treated with ConA alone (Fig. 7D). Despite ConA inducing massive damage of the

liver leading to the formation of large areas of necrosis, mice can survive more than KU-60019 price 3 days. This allowed us to test the therapeutic effect of IL-25 by injecting mice 6 hours after ConA administration, a time that was sufficient to cause liver damage (as shown in Fig. 7A,B). Mice treated with ConA and receiving IL-25 showed significantly reduced levels of transaminases, minimal macroscopic lesions, and less necrotic areas (Fig. 7E,F), as compared to mice treated with ConA and receiving PBS. In a final set of studies, we analyzed IL-25 protein expression in paraffin-embedded selleck products liver sections of patients with FH and controls by confocal IF. IL-25-positive cells were clearly evident in control livers, particularly in hepatocytes, SDHB but staining was markedly reduced in liver sections from patients with FH (Fig. 8), thus confirming that acute hepatocyte damage is associated with decreased production of IL-25. IL-25 (also known as IL-17E), a

member of the IL-17 cytokine gene family, is made by several immune and nonimmune cell types and plays a critical role in expansion of Th2 cell responses and negative regulation of both Th1 and Th17 immunity.[8, 9, 13, 14] Deregulation of IL-25 production has been described in many inflammatory disorders and is supposed to contribute to the progression of the pathology.[8, 9, 13, 14] For example, high IL-25 sustains inflammation in airways of patients with asthma, whereas defective IL-25 synthesis helps perpetuate chronic inflammation in the gut of patients with inflammatory bowel disease.[9, 26] This later finding fits with the demonstration that IL-25 delivers negative signals to macrophages and DCs with the downstream effect of suppressing detrimental inflammatory responses in the gut.[9] The data in the present study expand on these data and indicate that IL-25 is produced in both human and mouse liver. Despite its ability to amplify Th2 cell programs, IL-25 does not polarize Th cell responses along the Th2 pathway.[8, 26] Therefore, it is not surprising that expression of IL-25 in the uninjured liver was associated with no induction of Th2 cytokines.