Published online before print December 4, 2003
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agonists on T lymphocytes derived from MS patients
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*Department of Neurology, University of Bonn, Germany; and Department of Anesthesiology, University of Illinois, Chicago
@ To whom correspondence should be addressed. E-mail: m.heneka{at}uni-bonn.de.
Peroxisomal proliferator-activated receptors (PPARs) belong to a nuclear receptor superfamily of ligand-activated transcription factors. The PPAR-
isoform is expressed in human T lymphocytes, and oral administration of PPAR- agonists ameliorates the clinical course and histopathological features in experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis, suggesting a potential role for PPAR- agonists in the treatment of autoimmune diseases. To assess a potential therapeutic role of PPAR- agonists in multiple sclerosis, we compared the immunomodulatory effects of the thiazolidinedione (TZD) drugs pioglitazone (PIO) and ciglitazone and the non-TZD PPAR- agonist GW347845 on human T leukemia cells (Jurkat cells) and phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMCs) derived from 21 multiple sclerosis patients and 12 healthy donors. PIO, ciglitazone, and GW347845 suppressed PHA-induced T cell proliferation by 40-50% and secretion of interferon- and tumor necrosis factor 
, by 30-50%. Inhibition of proliferation was increased to 
80% and that of proinflammatory cytokine secretion, to 80-90% when PBMCs were first preincubated with PPAR- agonists and re-exposed at the time of PHA stimulation, indicating a sensitizing effect of PPAR- agonists. Inhibition of proliferation was also observed in the tetanus toxoid-specific T cell line KHS.TT2, albeit to a lesser extent. The antiproliferative effects of PIO and GW347845 were accompanied by a decrease of cell viability. Electron microscopy and Western blot analysis revealed DNA condensation and down-regulation of bcl-2, suggesting the induction of apoptosis in activated T lymphocytes. In summary, the data support the potential use of PPAR- agonists as immunomodulatory, therapeutic agents for autoimmune diseases.
Key Words:
EAE • IFN- • TNF-
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