Antagonizing Peroxisome Proliferator-Activated Receptor α Activity Selectively Enhances Th1 Immunity in Male Mice
| Autor: | Shannon E. Dunn, Ryan C. Clark, Thirumahal Selvanantham, Thierry Mallevaey, Nick Stock, Fei Linda Zhao, Lucia Correa, Jeeyoon Jennifer Ahn, Monan Angela Zhang, David Spaner |
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| Rok vydání: | 2015 |
| Předmět: |
Male
medicine.medical_specialty Immunology Peroxisome proliferator-activated receptor Pyridinium Compounds Biology CD8-Positive T-Lymphocytes Histones Interferon-gamma Mice Sex Factors Fenofibrate Internal medicine Gene expression medicine Immunology and Allergy Animals Nuclear Receptor Co-Repressor 1 PPAR alpha RNA Small Interfering Receptor chemistry.chemical_classification Mice Knockout Gene knockdown Acrylamides Acetylation Th1 Cells Natural killer T cell Listeria monocytogenes Mice Inbred C57BL Endocrinology chemistry Nuclear receptor Natural Killer T-Cells RNA Interference Corepressor CD8 |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950). 195(11) |
| ISSN: | 1550-6606 |
| Popis: | Females exhibit more robust Th1 responses than males. Our previous work suggested that this sex disparity is a consequence of higher activity of the androgen-induced gene peroxisome proliferator–activated receptor α (PPARα) in male CD4+ T cells. The objective of this study was to elucidate the cellular and molecular mechanism of how PPARα inhibits Th1 responses in male mice. In this study, we found that PPARα functions within CD4+ and CD8+ T lymphocytes and NKT cells to negatively regulate IFN-γ responses in male mice and identified Ifng as the gene target of PPARα repression. Treatment of male CD4+ T cells with the PPARα agonist fenofibrate induced the recruitment of PPARα and the nuclear receptor-interacting protein, nuclear receptor corepressor 1, to specific cis-regulatory elements in the Ifng locus. This recruitment associated with reduced histone acetylation at these sites. Knockdown of nuclear receptor corepressor 1 in primary male T cells abolished the effect of fenofibrate in reducing IFN-γ production. In contrast, treatment of male T cells with IS001, a novel antagonist of PPARα, increased Ifng gene expression and histone acetylation across the Ifng locus. Finally, we investigated the effects of IS001 on IFN-γ responses in mice during infection with the Th1-associated pathogen Listeria monocytogenes and observed that IS001 enhanced IFN-γ production by NKT, CD4+, and CD8+ T cells and improved the survival of male, but not female, mice. Our findings provide a novel mechanism of why IFN-γ responses are more robust in females and introduce a small-molecule IS001 that can be used to enhance Th1 immunity in males. |
| Databáze: | OpenAIRE |
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