[en] The peroxisome proliferator-activated receptor gamma (PPAR-gamma) belongs to a receptor superfamily of ligand-activated transcription factors involved in the regulation of metabolism and inflammation. Oral administration of PPAR-gamma agonists ameliorates the clinical course and histopathological features in experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis (MS), and PPAR-gamma agonist treatment of PBMCs from MS patients suppresses PHA-induced cell proliferation and cytokine secretion. These effects are pronounced when cells are preincubated with the PPAR-gamma agonists and reexposed at the time of stimulation, indicating a sensitizing effect. To characterize the mechanisms underlying this sensitizing effect, we analyzed PPAR-gamma expression in PMBCs of MS patients and healthy controls. Surprisingly, MS patients exhibited decreased PPAR-gamma levels compared with controls. PHA stimulation of PBMCs from healthy controls resulted in a significant loss of PPAR-gamma, which was prevented by in vitro preincubation of the cells or in vivo by long-term oral medication with the PPAR-gamma agonist pioglitazone. Differences in PPAR-gamma expression were accompanied by changes in PPAR-gamma DNA-binding activity, as preincubation with pioglitazone increased DNA binding of PPAR-gamma. Additionally, preincubation decreased NF-kappaB DNA-binding activity to control levels, whereas the inhibitory protein IkappaBalpha was increased. In MS patients, pioglitazone-induced increase in PPAR-gamma DNA-binding activity and decrease in NF-kappaB DNA-binding activity was only observed in the absence of an acute MS relapse. These results suggest that the sensitizing effect observed in the preincubation experiments is mediated by prevention of inflammation-induced suppression of PPAR-gamma expression with consecutive increase in PPAR-gamma DNA-binding activity.
Disciplines :
Neurologie
Auteur, co-auteur :
Klotz, Luisa; Department of Neurology, University of Bonn, Germany
Schmidt, Martina; Department of Neurology, University of Bonn, Germany
Giese, Thomas; Department of Immunology, University of Heidelberg, Germany
Sastre, Magdalena; Department of Neurology, University of Bonn, Germany
Knolle, Percy; Institute of Molecular Medicine and Experimental Immunology, University of Bonn, Germany
Klockgether, Thomas; Department of Neurology, University of Bonn, Germany
HENEKA, Michael ; Department of Neurology, University of Münster, Munster, Germany ; Department of Neurology, University of Münster, 48149 Munster, Germany
Co-auteurs externes :
yes
Langue du document :
Anglais
Titre :
Proinflammatory stimulation and pioglitazone treatment regulate peroxisome proliferator-activated receptor gamma levels in peripheral blood mononuclear cells from healthy controls and multiple sclerosis patients.
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