Effects of 15-deoxy-delta12,14-prostaglandin J2 (15d-PGJ2) and rosiglitazone on human gammadelta2 T cells.
BACKGROUND
Thiazolidinediones (TZD) class of drugs, and 15-deoxy-D12,14-prostaglandin J2 (15d-PGJ2) are immune regulators predicted to modulate human autoimmune disease. Their effects on gammadelta T cells, which are involved in animal model and human and animal autoimmune diseases, are unknown.


RESULTS
We characterized the activity of rosiglitazone (from the TZD class of drugs) and 15d-PGJ2 in human Vdelta2 T cells. We found that 15d-PGJ2 and rosiglitazone had different effects on Vdelta2 T cell functions. Both 15d-PGJ2 and rosiglitazone suppressed Vdelta2 T cell proliferation in response to IPP and IL2. However, only 15d-PGJ2 suppressed functional responses including cytokine production, degranulation and cytotoxicity against tumor cells. The mechanism for 15d-PGJ2 effects on Vdelta2 T cells acts through inhibiting Erk activation. In contrast, rosiglitazone did not affect Erk activation but the IL2 signaling pathway, which accounts for rosiglitazone suppression of IL2-dependent, Vdelta2 T cell proliferation without affecting TCR-dependent functions. Rosiglitazone and 15d-PGJ2 are designed to be peroxisome proliferator-activated receptor gamma (PPARgamma) ligands and PPARgamma was expressed in Vdelta2 T cell. Surprisingly, when PPARgamma levels were lowered by specific siRNA, 15d-PGJ2 and rosiglitazone were still active, suggesting their target of action induces cellular proteins other than PPARgamma.


CONCLUSIONS
The current findings expand our understanding of how the immune system is regulated by rosiglitazone and 15d-PGJ2 and will be important to evaluate these compounds as therapeutic agents in human autoimmune disease.
Li
Haishan
H
Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
Pauza
C David
CD
D000818:Animals; D001327:Autoimmune Diseases; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008024:Ligands; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000378:metabolism; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism*; D000077154:Rosiglitazone; D050799:STAT5 Transcription Factor / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects*; D045162:Thiazolidinediones / Q000494:pharmacology*
C477819:15-deoxyprostaglandin J2; D016207:Cytokines; D007004:Hypoglycemic Agents; D008024:Ligands; D016692:Receptors, Antigen, T-Cell, gamma-delta; D050799:STAT5 Transcription Factor; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D048049:Extracellular Signal-Regulated MAP Kinases; D015230:Prostaglandin D2