Inhibition of glial cell proinflammatory activities by peroxisome proliferator-activated receptor gamma agonist confers partial protection during antimyelin oligodendrocyte glycoprotein demyelination in vitro.
Peroxisome proliferator-activated receptor gamma (PPAR-gamma) is a member of the nuclear hormone superfamily originally characterized as a regulator of adipocyte differentiation and lipid metabolism. In addition, PPAR-gamma has important immunomodulatory functions. If the effect of PPAR-gamma's activation in T-cell-mediated demyelination has been recently demonstrated, nothing is known about the role of PPAR-gamma in antibody-induced demyelination in the absence of T-cell interactions and monocyte/macrophage activation. Therefore, we investigated PPAR-gamma's involvement by using an in vitro model of inflammatory demyelination in three-dimensional aggregating rat brain cell cultures. We found that PPAR-gamma was not constitutively expressed in these cultures but was strongly up-regulated following demyelination mediated by antibodies directed against myelin oligodendrocyte glycoprotein (MOG) in the presence of complement. Pioglitazone, a selective PPAR-gamma agonist, partially protected aggregates from anti-MOG demyelination. Heat shock responses and the expression of the proinflammatory cytokine tumor necrosis factor-alpha were diminished by pioglitazone treatment. Therefore, pioglitazone protection seems to be linked to an inhibition of glial cell proinflammatory activities following anti-MOG induced demyelination. We show that PPAR-gamma agonists act not only on T cells but also on antibody-mediated demyelination. This may represent a significant benefit in treating multiple sclerosis patients.
Duvanel
Cécile Besson
CB
Neurochemistry Laboratory, Department of Pediatrics, CHUV, Lausanne, Switzerland.
Honegger
Paul
P
Pershadsingh
Harrihar
H
Feinstein
Douglas
D
Matthieu
Jean-Marie
JM
D000704:Analysis of Variance; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003165:Complement System Proteins / Q000276:immunology; D003459:Crystallins / Q000187:drug effects / Q000378:metabolism; D003711:Demyelinating Diseases / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000235:genetics / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000187:drug effects / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing); D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007074:Immunoglobulin G / Q000494:pharmacology; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000502:physiology; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D009457:Neuroglia / Q000187:drug effects* / Q000502:physiology; D010105:Oxygenases; D000077205:Pioglitazone; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists* / Q000235:genetics / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation
D000911:Antibodies, Monoclonal; D003459:Crystallins; D006360:Heat-Shock Proteins; D007004:Hypoglycemic Agents; D007074:Immunoglobulin G; D018836:Inflammation Mediators; C571328:Mog protein, rat; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D003165:Complement System Proteins; D010105:Oxygenases; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D000077205:Pioglitazone