prostaglandin-d2 and nimesulide

Cyclooxygenase (COX)-2 selective inhibitors suppress non-alcoholic fatty liver disease (NAFLD); however, the precise mechanism of action remains unknown. The aim of this study was to examine how the COX-2 selective inhibitor nimesulide suppresses NAFLD in a murine model of high-fat diet (HFD)‑induced obesity. Mice were fed either a normal chow diet (NC), an HFD, or HFD plus nimesulide (HFD-nime) for 12 weeks. Body weight, hepatic COX-2 mRNA expression and triglyceride accumulation were significantly increased in the HFD group. Triglyceride accumulation was suppressed in the HFD-nime group. The mRNA expression of hepatic peroxisome proliferator-activated receptor γ (PPARγ) and the natural PPARγ agonist 15-deoxy-Δ12,14-prostaglandin J2 (15d‑PGJ2) were significantly increased in the HFD group and significantly suppressed in the HFD-nime group. Glucose metabolism was impaired in the HFD group compared with the NC group, and it was significantly improved in the HFD-nime group. In addition, the plasma insulin levels in the HFD group were increased compared with those in the NC group, and were decreased in the HFD-nime group. These results indicate that HFD-induced NAFLD is mediated by the increased hepatic expression of COX-2. We suggest that the production of 15d-PGJ2, which is mediated by COX-2, induces NAFLD and hepatic insulin resistance by activating PPARγ. Furthermore, the mRNA expression of tissue inhibitor of metalloproteinases-1 (TIMP‑1), procollagen-1 and monocyte chemoattractant protein-1 (MCP-1), as well as the number of F4/80-positive hepatic (Kupffer) cells, were significantly increased in the HFD group compared with the NC group, and they were reduced by nimesulide. In conclusion, COX-2 may emerge as a molecular target for preventing the development of NAFLD and insulin resistance in diet-related obesity.

Topics: Animals; Chemokine CCL2; Collagen Type I; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Diet, High-Fat; Gene Expression; Glucose; Immunohistochemistry; Insulin; Insulin Resistance; Kupffer Cells; Liver; Male; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Obesity; PPAR gamma; Prostaglandin D2; Reverse Transcriptase Polymerase Chain Reaction; Sulfonamides; Tissue Inhibitor of Metalloproteinase-1; Triglycerides

Prostaglandins (PG) are well known lipid mediators with important immunoregulatory properties. While exogenous PGE2 has the ability to modulate the function and maturation of antigen presenting cells, such as dendritic cells (DC), it is not clear whether human DC have the capacity to synthesize PGE2 and other prostaglandins themselves. We therefore examined the expression of inducible cyclo-oxygenase (COX-2) by monocyte derived DC and the production of PGE2 and PGD2. Both monocyte derived DC and freshly isolated blood myeloid DC expressed little COX-2 constitutively, though COX-2 expression was rapidly but transiently upregulated in response to lipopolysaccharide stimulation. COX-2 mRNA was detectable within 1 h of LPS exposure, peaked at 4-6 h, and rapidly declined thereafter. COX-2 expression was accompanied by DC synthesis of PGE2, with peak levels present at 6-18 h post-stimulation. In contrast, PGD2 synthesis was not detected at any time point. When DC were activated with LPS in the presence of nimesulide, a COX-2 selective inhibitor, IL-10 synthesis was inhibited, indicating that endogenous prostaglandins regulate DC cytokine production. PGE2 production by DC may therefore modulate DC and T-cell function, thereby shaping the character of the immune response.

Topics: Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dendritic Cells; Dinoprostone; Flow Cytometry; Humans; Immunohistochemistry; Interleukin-10; Isoenzymes; Lipopolysaccharides; Membrane Proteins; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases; RNA, Messenger; Sulfonamides

Nimesulide (NIM) is a sulfonanilide nonsteroidal anti-inflammatory drug (NSAID) used in the treatment of various inflammatory diseases and chemically unrelated to other acidic NSAIDs, such as acetylsalicylic acid (ASA) and indomethacin (INDO). We investigated the effects of NIM and of its in vivo metabolite, 4-hydroxy-NIM (OH-NIM), on the release of performed (histamine) and de novo synthesized mediators (sulfidopeptide leukotriene C4 [LTC4] and prostaglandin D2 [PGD2]) from human basophils and mast cells isolated from lung parenchyma (HLMC) and skin (HSMC). Histamine release from basophils challenged with rabbit anti-human IgE antibody (anti-IgE) was enhanced by preincubation with ASA or INDO (92.2 +/- 7.1% at 10(-3) M and 61.1 +/- 6.7% at 3 x 10(-6) M, respectively; P < .001). In contrast, NIM and its metabolite, OH-NIM (10(-6) to 10(-3) M), caused concentration-dependent inhibition (2.9 to approximately 60% and 3.7 to approximately 90%, respectively) of IgE-mediated histamine release from basophils. NIM and OH-NIM also inhibited histamine release from basophils induced by the Ca++ ionophore A23187 and different protein kinase C activators, such as 12-O-tetradecanoyl-phorbol-13-acetate, bryostatin 1 and bryostatin 5. NIM and OH-NIM also inhibited the IgE-mediated histamine release from HLMC (52.3 +/- 9.6% and 66.1 +/- 12.1% at 10(-3) M, respectively; P < .0001) and HSMC (67.3 +/- 3.7% and 77.7 +/- 12.0% at 10(-3) M, respectively; P < .0001) but had little or no effect on HLMC and HSMC activated by A23187. NIM (10(-6) to 10(-3) M) markedly inhibited the de novo synthesis of LTC4 from basophils, LTC4 and PGD2 from HLMC and PGD2 from HSMC. NIM and OH-NIM potentiated, whereas ASA and INDO reversed, the inhibitory effect of adenylate cyclase agonists, such as prostaglandin E1 and forskolin. In addition, NIM and OH-NIM reversed the enhancing effects of ASA and INDO on IgE-mediated histamine release from basophils.

Topics: Adolescent; Adult; Alprostadil; Amino Acid Sequence; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Basophils; Bryostatins; Calcimycin; Colforsin; Complement C5a; Histamine Release; Humans; Immunoglobulin E; Indomethacin; Lactones; Leukotriene C4; Lung; Macrolides; Mast Cells; Middle Aged; Molecular Sequence Data; N-Formylmethionine Leucyl-Phenylalanine; Prostaglandin D2; Skin; Sulfonamides; Tetradecanoylphorbol Acetate