Crosstalk between PPARγ Ligands and Inflammatory-Related Pathways in Natural T-Regulatory Cells from Type 1 Diabetes Mouse Model

• Published in: Biomolecules (Basel, Switzerland) Vol. 8; no. 4; p. 135
• Main Authors: Nor Effa, S Zulkafli, Yaacob, Nik Soriani, Mohd Nor, Norazmi
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 05.11.2018; MDPI
• Subjects: Animals; Antigen (tumor-associated); Antigens, CD - metabolism; Autoantigens; autoimmune diabetes; Cell Separation; Cell therapy; ciglitazone; Diabetes; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - immunology; Disease Models, Animal; Effector cells; Encephalomyelitis; Female; Forkhead protein; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Foxp3; Foxp3 protein; Gene expression; Gene Expression Regulation; immune regulation; Immunological tolerance; Immunomodulation; immunomodulator; Immunoregulation; Immunosuppressive agents; Immunotherapy; Inflammation; Inflammation - genetics; Inflammation - immunology; Ligands; Lymphocytes; Lymphocytes T; Mice, Inbred NOD; NOD mouse; Peroxisome proliferator-activated receptors; Phosphorylation; PPAR gamma - metabolism; PPARγ; Protein Binding; Response Elements - genetics; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction; Software; STAT5 Transcription Factor - metabolism; T-Lymphocytes, Regulatory - immunology; T-Regulatory cells; thiazolidinediones; Transcription factors; Tumor microenvironment; Variance analysis; ZAP-70 Protein-Tyrosine Kinase - metabolism; Ann Arbor Michigan; United States > US; Germany; thiazolidinediones; immunomodulator; autoimmune diabetes; NOD mouse; T-Regulatory cells; Foxp3; PPARγ; immune regulation; ciglitazone
• ISSN: 2218-273X; 2218-273X
• DOI: 10.3390/biom8040135

Immunomodulation, as a means of immunotherapy, has been studied in major research and clinical laboratories for many years. T-Regulatory (Treg) cell therapy is one of the modulators used in immunotherapy approaches. Similarly, nuclear receptor peroxisome proliferator activated receptor gamma (PPARγ) has extensively been shown to play a role as an immuno-modulator during inflammation. Given their mutual roles in downregulating the immune response, current study examined the influence of PPARγ ligands i.e., thiazolidinedione (TZD) class of drugs on Forkhead Box P3 (Foxp3) expression and possible crosstalk between PPARγ and nTreg cells of Non-Obese Diabetes (NOD) and Non-Obese Diabetes Resistant (NOR) mice. Results showed that TZD drug, ciglitazone and natural ligand of PPARγ 15d-prostaglandin downregulated Foxp3 expression in activated nTreg cells from both NOD and NOR mice. Interestingly, addition of the PPARγ inhibitor, GW9662 further downregulated Foxp3 expression in these cells from both mice. We also found that PPARγ ligands negatively regulate Foxp3 expression in activated nTreg cells via PPARγ-independent mechanism(s). These results demonstrate that both natural and synthetic PPARγ ligands capable of suppressing Foxp3 expression in activated nTreg cells of NOD and NOR mice. This may suggest that the effect of PPARγ ligands in modulating Foxp3 expression in activated nTreg cells is different from their reported effects on effector T cells. Given the capability to suppress Foxp3 gene, it is possible to be tested as immunomodulators in cancer-related studies. The co-lateral use of PPARγ ligands in nTreg cells in inducing tolerance towards pseudo-self antigens as in tumor microenvironment may uphold beneficial outcomes.