15-deoxyprostaglandin-j2 and Colitis

Bone marrow mesenchymal stem cells (BMMSCs) have been used to treat a variety of autoimmune diseases in clinics. However, the therapeutic effects are largely dependent on the immunomodulatory capacity of culture-expanded BMMSCs. In the present study, we show that aspirin (acetylsalicylic acid, ASA)-treated BMMSCs have significantly improved immunomodulatory function, as indicated by upregulation of regulatory T cells (Tregs) and downregulation of Th17 cells via the 15d-PGJ2/PPARγ/TGF-β1 pathway. Furthermore, the therapeutic effect of ASA-pretreated BMMSCs was confirmed in a dextran sodium sulfate-induced experimental colitis mouse model, in which systemic infusion of ASA-pretreated BMMSCs significantly ameliorated disease activity index and colonic inflammation, along with an increased number of Tregs and decreased number of Th17 cells. Taken together, our results suggest that aspirin treatment is a feasible strategy to promote BMMSC-based immunomodulation.

Topics: Animals; Apoptosis; Aspirin; Cell Proliferation; Cells, Cultured; Coculture Techniques; Colitis; Dinoprostone; Female; Immunomodulation; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice, Inbred C57BL; PPAR gamma; Prostaglandin D2; Signal Transduction; T-Lymphocytes, Regulatory; Th17 Cells; Transforming Growth Factor beta1

Psychological stress has been implicated in the clinical course of several gastrointestinal diseases, but the mechanisms implicated and the effects of stress on the normal colon are not yet fully understood.. Male Wistar rats were exposed to various immobilization periods as a stress paradigm. Colon was processed to assess myeloperoxidase activity, nitric oxide synthase 2, cyclooxygenase 2, and peroxisome proliferator-activated receptor gamma (PPARgamma) expression and production of prostaglandins. Colonic permeability, bacterial translocation, tight junctions ultrastructure, and immunoglobulin (Ig) A levels were also evaluated.. Exposure to acute (6 hours) immobilization stress produced an increase in myeloperoxidase activity and nitric oxide synthase 2 and cyclooxygenase 2 expression. All these parameters remained increased after 5 days of repeated stress exposure, showing a trend to normalize after 10 days. Levels of the anti-inflammatory eicosanoid 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) and expression of PPARgamma run parallel with these changes. Colonic epithelial barrier was altered after stress exposure, and a significant decrease in colonic IgA levels after acute stress exposure was observed. Pretreatment with PPARgamma agonists 15d-PGJ(2) and rosiglitazone prevented colonic inflammation and barrier dysfunction as well as the decrease of IgA production induced after acute stress; PPARgamma specific antagonist T0070907 reverted these effects.. Activation of PPARgamma in rat colon in vivo seems to counteract colonic inflammation and dysfunction induced by stress. On the other hand, PPARgamma ligands may be therapeutically useful in conditions in which inflammation and barrier dysfunction takes place in colon after exposure to stress.

Topics: Animals; Bacterial Translocation; Benzamides; Colitis; Colon; Corticosterone; Cyclooxygenase 2; Gene Expression Regulation, Enzymologic; Homeostasis; Intestinal Absorption; Ligands; Male; Nitric Oxide Synthase Type II; Peroxidase; PPAR gamma; Prostaglandin D2; Pyridines; Rats; Rats, Wistar; Restraint, Physical; Rosiglitazone; Stress, Physiological; Thiazolidinediones

Curcumin is a widely used spice with anti-inflammatory and anti-cancer properties. It has been reported that curcumin held therapeutic effects on experimental colitis by inhibition of nuclear factor kappa B (NF-kappaB). The peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor with anti-tumor and anti-inflammatory effects and its activation may inhibit the nuclear translocation of NF-kappaB. Several studies have shown that PPARgamma ligands had an important therapeutic effect in colitis. However there is no report about the alteration of PPARgamma in trinitrobenzene sulphonic acid (TNBS)-induced colitis treated with curcumin. In this study, we administered curcumin (30 mg/kg/day) by intraperitoneal injection immediately after colitis was induced and the injection lasted for two weeks. have evaluated the effects of curcumin on the colitis induced by trinitrobenzene sulphonic acid (TNBS). Curcumin (30 mg/kg d) was administered by intraperitoneal just after colitis was induced and lasted for two weeks. Therapeutic effects of dexamethasone (Dex, 2 mg/kg d) alone and the combined effects of curcumin+Dex were also examined. We found that curcumin improved long-term survival rate of disease-bearing rats, promoted rat body weight recovery, and decreased macroscopic scores of the colitis. The expression levels of PPARgamma, 15-deoxy-D12,14-prostaglandin J(2) (15d-PGJ(2)) and prostaglandin E(2) (PGE(2)) were all increased, but the expression level of cyclooxygenase-2 (COX-2) was decreased in rats after administration of curcumin. Treatment with Dex improved PPARgamma expression and inhibited the expression of COX-2, 15d-PGJ(2) and PGE(2). Combined effects of curcumin+Dex were similar to that of Dex. In summary, curcumin showed therapeutic effects on TNBS-induced colitis and the mechanisms by which curcumin exerts its effects may involve activation of PPARgamma and its ligands.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Colitis; Colon; Curcumin; Cyclooxygenase 2; Cytokines; Dexamethasone; Dinoprostone; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Gene Expression; PPAR gamma; Prostaglandin D2; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Specific Pathogen-Free Organisms; Time Factors; Trinitrobenzenesulfonic Acid; Weight Loss

Colitis involves immune cell-mediated tissue injuries, but the contribution of epithelial cells remains largely unclear. Vanin-1 is an epithelial ectoenzyme with a pantetheinase activity that provides cysteamine/cystamine to tissue. Using the 2,4,6-trinitrobenzene sulfonic acid (TNBS)-colitis model we show here that Vanin-1 deficiency protects from colitis. This protection is reversible by administration of cystamine or bisphenol A diglycidyl ether, a peroxisome proliferator-activated receptor (PPAR)gamma antagonist. We further demonstrate that Vanin-1, by antagonizing PPARgamma, licenses the production of inflammatory mediators by intestinal epithelial cells. We propose that Vanin-1 is an epithelial sensor of stress that exerts a dominant control over innate immune responses in tissue. Thus, the Vanin-1/pantetheinase activity might be a new target for therapeutic intervention in inflammatory bowel disease.

Topics: Active Transport, Cell Nucleus; Amidohydrolases; Animals; Benzhydryl Compounds; Body Weight; Cell Adhesion Molecules; Cell Line; Cell Nucleus; Chemokine CCL2; Chemokine CXCL2; Chemokines; Colitis; Colon; Cyclooxygenase 2; Cystamine; Cytokines; Epithelial Cells; Epoxy Compounds; Gene Expression Regulation; GPI-Linked Proteins; Interleukin-1beta; Mice; Mice, Inbred BALB C; Mice, Knockout; Mice, SCID; PPAR gamma; Prostaglandin D2; Survival Analysis; Trinitrobenzenesulfonic Acid