Activation of PPARgamma enhances in vitro the immunosuppressive effect of cyclosporine on T lymphocytes.
BACKGROUND
Peroxisome Proliferator-Activated Receptor gamma (PPARgamma) is a nuclear receptor that regulates the transcription of genes associated with lipid and glucose metabolism. Recently, it has been shown that PPARgamma modulates the activity of T cells, resulting in inhibition of T cell proliferation and IL-2 release. In this study we investigated whether the PPARgamma 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 muM); (3) R (20 muM) 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.


CONCLUSIONS
PPARgamma ligand R potentiates in vitro the inhibitory action of CsA on activated T helper cells. The combined use of PPARgamma ligands and low-dose CsA represents a rationale therapeutic approach aimed to prevent CsA nephrotoxicity while maintaining adequate immunosuppression.
Rampino
Teresa
T
Unit of Nephrology, Dialysis and Transplantation, IRCCS Policlinico San Matteo and University, 27100 Pavia, Italy. t.rampino@smatteo.pv.it <t.rampino@smatteo.pv.it>
Ranghino
Andrea
A
Guidetti
Cristina
C
Gregorini
Marilena
M
Soccio
Grazia
G
Marasà
Maddalena
M
Libetta
Carmelo
C
Guida
Gianenrico
G
De Amici
Mara
M
Dal Canton
Antonio
A
D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007376:Interleukin-2 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D008213:Lymphocyte Activation / Q000187:drug effects; D047495:PPAR gamma / Q000187:drug effects* / Q000502:physiology; D000077154:Rosiglitazone; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D045162:Thiazolidinediones / Q000494:pharmacology*
D007166:Immunosuppressive Agents; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D016572:Cyclosporine