title: Licofelone inhibits interleukin-18-induced pro-inflammatory cytokine release and cellular proliferation in human mesangial cells.
abstract: Licofelone, a novel dual anti-inflammatory drug that inhibits 5-lipoxygenase (5-LOX) and cyclooxygenase (COX), has recently been defined to have therapeutic effects in osteoarthritis. Both 5-LOX and COX play functional roles in the pathogenesis of glomerulonephritis in children as well. Interleukin-18 is a pro-inflammatory cytokine. It remains unclear whether licofelone can ameliorate inflammatory response of human mesangial cells (HMC) exposed to interleukin-18. In this study, HMC were cultured and exposed to interleukin-18 with or without pre-treatment of licofelone. COX-2 and 5-LOX enzyme activities in mesangial cells were determined with chromometry or high-performance liquid chromatography. Prostaglandin E2, cysteinyl leukotriene, monocyte chemotactic protein-1 and interferon-γ concentrations in culture medium were measured using an enzyme-linked immunosorbent assay. Western blotting was employed to detect phosphorylated mitogen-activated protein kinases ERK1/2, p38 and JNK1/2 in HMC. It was found that licofelone attenuated interleukin-18-induced COX-2 enzyme activity in HMC and prostaglandin E2 release in a dose-dependent manner. Similarly, licofelone inhibited interleukin-18-induced 5-LOX enzyme activity and leukotriene release. Licofelone reduced interleukin-18-induced phosphorylation of p38 mitogen-activated protein kinase and suppressed monocyte chemotactic protein-1 and interferon-γ synthesis. Moreover, licofelone inhibited IL-18-induced proliferation of mesangial cells. We conclude that licofelone inhibits interleukin-18-induced pro-inflammatory cytokine release and cellular proliferation in HMC, which may represent a really interesting therapeutic approach for glomerulonephritis in children.
authors.affiliation: Department of Pediatrics, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Yuan-Jun
authors.initials: YJ
authors.lastname: Wu
authors.forename: Mei
authors.initials: M
authors.lastname: Xue
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
mesh_terms: D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D015153:Blotting, Western; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D018932:Chemokine CCL2 / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000209:etiology; D007371:Interferon-gamma / Q000378:metabolism; D020382:Interleukin-18 / Q000009:adverse effects* / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D050527:Mesangial Cells / Q000187:drug effects* / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D011758:Pyrroles / Q000494:pharmacology*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D018932:Chemokine CCL2; D052246:Cyclooxygenase 2 Inhibitors; D020382:Interleukin-18; D016859:Lipoxygenase Inhibitors; D011758:Pyrroles; D007371:Interferon-gamma; D001094:Arachidonate 5-Lipoxygenase; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C088092:licofelone