Results. MTX increased 27-hydroxylase message and completely blocked NS398-induced down-regulation of 27-hydroxylase (mean ؎ SEM 112.8 ؎ 13.1% for NS398 plus MTX versus 71.1 ؎ 4.3% for NS398 alone; P < 0.01). MTX also negated COX-2 inhibitor-mediated down-regulation of ABCA1. The ability of MTX to reverse inhibitory effects on 27-hydroxylase and ABCA1 was blocked by the adenosine A 2A receptor-specific antagonist ZM241385. MTX also prevented NS398 and IFN␥ from increasing transformation of lipid-laden THP-1 macrophages into foam cells.Conclusion. This study provides evidence supporting the notion of an atheroprotective effect of MTX. Through adenosine A 2A receptor activation, MTX promotes reverse cholesterol transport and limits foam cell formation in THP-1 macrophages. This is the first reported evidence that any commonly used medication can increase expression of antiatherogenic reverse cholesterol transport proteins and can counteract the effects of COX-2 inhibition. Our results suggest that one mechanism by which MTX protects against cardiovascular disease in rheumatoid arthritis patients is through facilitation of cholesterol outflow from cells of the artery wall.Methotrexate (MTX) has a long history of use in the treatment of various immunologic diseases, and has been used to treat rheumatoid arthritis (RA) and psoDr.

IL-33, a recently described member of the IL-1 family, has been identified as a cytokine endowed with pro-Th2 type functions. To date, there are only limited data on its role in physiological and pathological hepatic immune responses. In this study, we examined the role of IL-33 in immune-mediated liver injury by exploring the model of concanavalin A (Con A)-induced hepatitis. We observed that the level of IL-33 expression in the liver was dramatically increased at 12 h after Con A injection. Meanwhile, ST2L, the receptor of IL-33, was significantly up-regulated in lymphocytes including T and natural killer T (NKT) cells, especially in NKT cells. Moreover, administration of recombinant IL-33 exacerbated Con A-induced hepatitis, while pretreatment of IL-33-blocking antibody or psST2-Fc plasmids showed a protective effect probably by inhibiting the activation of late stage of T cells and NKT cells and also decreasing the production of the cytokine IFN-γ. Furthermore, depletion of NKT cells abolished the protective effect of IL-33-blocking antibody, and IL-33 failed to exacerbate Con A-induced hepatitis in IFN-γ(-/-) mice. These data suggested the critical roles of NKT cells and IFN-γ in the involvement of IL-33 in Con A-induced hepatitis. Blockade of IL-33 may represent a novel therapeutic strategy through IL-33/ST2L signal to prevent immune-mediated liver injury.

CD103+ dendritic cells (DCs) have been shown to play a crucial role in the pathogenesis of inflammatory bowel diseases (IBDs) through educating regulatory T (Treg) cells differentiation. However, the mechanism of CD103+ DCs subsets differentiation remains elusive. Interleukin (IL)-4 is a pleiotropic cytokine that is upregulated in certain types of inflammation, including IBDs and especially ulcerative colitis. However, the precise role of IL-4 in the differentiation of CD103+ DCs subpopulation remains unknown. In this study, we observed a repressive role of IL-4 on the CD103+ DCs differentiation in both mouse and human. High-dose IL-4 inhibited the CD103+ DC differentiation. In comparison to CD103− DCs, CD103+ DCs expressed high levels of the co-stimulatory molecules and indoleamine 2,3-dioxygenase (IDO). Interestingly, IL-4 diminished IDO expression on DCs in a dose-dependent manner. Besides, high-dose IL-4-induced bone marrow-derived DCs, and monocyte-derived DCs revealed mature DCs profiles, characterized by increased co-stimulatory molecules and decreased pinocytotic function. Furthermore, DCs generated under low concentrations of IL-4 favored Treg cells differentiation, which depend on IDO produced by CD103+ DCs. Consistently, IL-4 also reduced the frequency of CD103+ DC in vivo. Thus, we here demonstrated that the cytokine IL-4 involved in certain types of inflammatory diseases by orchestrating the functional phenotype of CD103+ DCs subsets.

Background: Currently, active ingredients of herbal extracts that can suppress lipid accumulation in the liver have been considered a potential treatment option for nonalcoholic fatty liver disease. Methods: Steatosis rat model was created by high fat and high sucrose diet feeding and treated with oxymatrine (OMT). Serum biochemical parameters, liver histology and lipid profiles were examined. Hepatic differentially expressed proteins (DEPs) which were significantly changed by OMT treatment were identified by iTRAQ analysis. The expressions of representative DEPs, Sirt1 and AMPKα were evaluated by western blotting. Results: OMT significantly reduced the body weight and liver weight of steatosis animals, decreased the serum levels of triglyceride and total cholesterol as well as the hepatic triglyceride and free fatty acid levels, and effectively alleviated fatty degeneration in the liver. A list of OMT-related DEPs have been screened and evaluated by bioinformatics analysis. OMT significantly decreased the expressions of L-FABP, Plin2, FASN and SCD1 and increased Sirt1 expression and AMPKα phosphorylation in the liver of rats with steatosis. Conclusion: The present study has confirmed the significant efficacy of OMT for improving steatosis and revealed hepatic proteomic changes and Sirt1/AMPK signaling activation by OMT treatment in rats with steatosis.