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Anti‐inflammatory and antiproliferative actions of PPAR‐γ agonists on T lymphocytes derived from MS patients
Author(s) -
Schmidt Stephan,
Moric Edin,
Schmidt Martina,
Sastre Magdalena,
Feinstein Douglas L.,
Heneka Michael T.
Publication year - 2004
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0803402
Subject(s) - ciglitazone , biology , experimental autoimmune encephalomyelitis , jurkat cells , peroxisome proliferator activated receptor , endocrinology , medicine , proinflammatory cytokine , receptor , ppar agonist , thiazolidinedione , cytokine , immunology , t cell , inflammation , immune system , biochemistry , type 2 diabetes , diabetes mellitus
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.