Activation of PPARgamma enhances in vitro the immunosuppressive effect of cyclosporine on T lymphocytes

Background: Peroxisome Proliferator-Activated Receptor ! (PPAR! ) is a nuclear receptor that regulates the transcription of genes associated with lipid and glucose metabolism. Recently, it has been shown that PPAR! modulates the activity of T cells, resulting in inhibition of T cell proliferation and IL-2 release. In this study we investigated whether the PPAR! ligand rosiglitazone (R) enhances in vitro the immunosuppressive effects of cyclosporine A (CsA). Methods: CD4 + T cells isolated from peripheral blood mononuclear cells of healthy donors were activated either with mitogens or by one-way mixed lymphocyte reaction. The activated T cells were treated with (1) CsA at low and high concentration (50, 150 ng/ml); (2) R (20 " M); (3) R (20 " M) in combination with CsA at low concentration (50 ng/ml). We studied the effects of the various treatments on cell proliferation (incorporation of [ 3 H] thymidine), the cell-cycle phases (FACS analysis), IL-2 release (ELISA), and IL-2 receptor (CD25) expression (FACS analysis). Results: R used alone reduced T cell proliferation and CD25 expression. Low-dose CsA combined with R was significantly more powerful than either high-dose CsA alone or R alone in suppressing IL-2 release, arresting the T cell cycle, and blocking the growth of activated T cells. Conclusion: PPAR! ligand R potentiates in vitro the inhibitory action of CsA on activated T helper cells. The combined use of PPAR! ligands and low-dose CsA represents a rationale therapeutic approach aimed to prevent CsA nephrotoxicity while maintaining adequate immunosuppression. © 2007 Elsevier B.V. All rights reserved.