J Leukoc Biol. 2003 Dec 4
Schmidt S, Moric E, Schmidt M, Sastre M, Feinstein DL, Heneka MT.
Department of Neurology, University of Bonn, Germany; and ()Department of Anesthesiology, University of Illinois, Chicago.
Peroxisomal proliferator-activated receptors (PPARs) belong to a nuclear receptor superfamily of ligand-activated transcription factors.
The PPAR-gamma isoform is expressed in human T lymphocytes, and oral administration of PPAR-gamma agonists ameliorates the clinical course and histopathological features in experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis, suggesting a potential role for PPAR-gamma agonists in the treatment of autoimmune diseases.
To assess a potential therapeutic role of PPAR-gamma agonists in multiple sclerosis, we compared the immunomodulatory effects of the thiazolidinedione (TZD) drugs pioglitazone (PIO) and ciglitazone and the non-TZD PPAR-gamma 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-gamma and tumor necrosis factor alpha, by 30-50%.
Inhibition of proliferation was increased to approximately 80% and that of proinflammatory cytokine secretion, to 80-90% when PBMCs were first preincubated with PPAR-gamma agonists and re-exposed at the time of PHA stimulation, indicating a sensitizing effect of PPAR-gamma 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-gamma agonists as immunomodulatory, therapeutic agents for autoimmune diseases.