RESUMO
By using an in vitro model of antibody-mediated demyelination, we investigated the relationship between tumor necrosis factor-alpha (TNF-alpha) and heat shock protein (HSP) induction with respect to oligodendrocyte survival. Differentiated aggregate cultures of rat telencephalon were subjected to demyelination by exposure to antibodies against myelin oligodendrocyte glycoprotein (MOG) and complement. Cultures were analyzed 48 hr after exposure. Myelin basic protein (MBP) expression was greatly decreased, but no evidence was found for either necrosis or apoptosis. TNF-alpha was significantly up-regulated. It was localized predominantly in neurons and to a lesser extent in astrocytes and oligodendrocytes, and it was not detectable in microglial cells. Among the different HSPs examined, HSP32 and alphaB-crystallin were up-regulated; they may confer protection from oxidative stress and from apoptotic death, respectively. These results suggest that TNF-alpha, often regarded as a promoter of oligodendroglial death, could alternatively mediate a protective pathway through alphaB-crystallin up-regulation.
Assuntos
Anticorpos/efeitos adversos , Cristalinas/metabolismo , Doenças Desmielinizantes/metabolismo , Oligodendroglia/efeitos dos fármacos , Telencéfalo/citologia , Fator de Necrose Tumoral alfa/metabolismo , 2',3'-Nucleotídeo Cíclico Fosfodiesterases/metabolismo , Animais , Apoptose/fisiologia , Western Blotting/métodos , Células Cultivadas , Proteínas do Sistema Complemento/efeitos adversos , Doenças Desmielinizantes/induzido quimicamente , Modelos Animais de Doenças , Interações Medicamentosas , Embrião de Mamíferos , Proteína Glial Fibrilar Ácida/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Heme Oxigenase-1 , Imuno-Histoquímica/métodos , Hibridização In Situ/métodos , Proteína Básica da Mielina/genética , Proteína Básica da Mielina/metabolismo , Proteínas da Mielina , Glicoproteína Associada a Mielina/imunologia , Glicoproteína Mielina-Oligodendrócito , Necrose/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Regulação para CimaRESUMO
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.