In:
Journal of Leukocyte Biology, Oxford University Press (OUP), Vol. 75, No. 3 ( 2004-03-01), p. 478-485
Abstract:
Peroxisomal proliferator-activated receptors (PPARs) belong to a nuclear receptor superfamily of ligand-activated transcription factors. The PPAR-γ isoform is expressed in human T lymphocytes, and oral administration of PPAR-γ agonists ameliorates the clinical course and histopathological features in experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis, suggesting a potential role for PPAR-γ agonists in the treatment of autoimmune diseases. To assess a potential therapeutic role of PPAR-γ agonists in multiple sclerosis, we compared the immunomodulatory effects of the thiazolidinedione (TZD) drugs pioglitazone (PIO) and ciglitazone and the non-TZD PPAR-γ 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-γ and tumor necrosis factor α, 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-γ agonists and re-exposed at the time of PHA stimulation, indicating a sensitizing effect of PPAR-γ 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-γ agonists as immunomodulatory, therapeutic agents for autoimmune diseases.
Type of Medium:
Online Resource
ISSN:
0741-5400
,
1938-3673
Language:
English
Publisher:
Oxford University Press (OUP)
Publication Date:
2004
detail.hit.zdb_id:
2026833-6
SSG:
12
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