In:
The Journal of Immunology, The American Association of Immunologists, Vol. 175, No. 8 ( 2005-10-15), p. 4948-4955
Abstract:
The peroxisome proliferator-activated receptor γ (PPAR-γ) belongs to a receptor superfamily of ligand-activated transcription factors involved in the regulation of metabolism and inflammation. Oral administration of PPAR-γ agonists ameliorates the clinical course and histopathological features in experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis (MS), and PPAR-γ 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-γ agonists and reexposed at the time of stimulation, indicating a sensitizing effect. To characterize the mechanisms underlying this sensitizing effect, we analyzed PPAR-γ expression in PMBCs of MS patients and healthy controls. Surprisingly, MS patients exhibited decreased PPAR-γ levels compared with controls. PHA stimulation of PBMCs from healthy controls resulted in a significant loss of PPAR-γ, which was prevented by in vitro preincubation of the cells or in vivo by long-term oral medication with the PPAR-γ agonist pioglitazone. Differences in PPAR-γ expression were accompanied by changes in PPAR-γ DNA-binding activity, as preincubation with pioglitazone increased DNA binding of PPAR-γ. Additionally, preincubation decreased NF-κB DNA-binding activity to control levels, whereas the inhibitory protein IκBα was increased. In MS patients, pioglitazone-induced increase in PPAR-γ DNA-binding activity and decrease in NF-κB 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-γ expression with consecutive increase in PPAR-γ DNA-binding activity.
Type of Medium:
Online Resource
ISSN:
0022-1767
,
1550-6606
DOI:
10.4049/jimmunol.175.8.4948
Language:
English
Publisher:
The American Association of Immunologists
Publication Date:
2005
detail.hit.zdb_id:
1475085-5
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