Pharmacological Inhibition of Bromodomain Proteins Suppresses Retinal Inflammatory Disease and Downregulates Retinal Th17 Cells
| العنوان: | Pharmacological Inhibition of Bromodomain Proteins Suppresses Retinal Inflammatory Disease and Downregulates Retinal Th17 Cells |
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| المؤلفون: | Malihe Eskandarpour, Robert A. Alexander, Virginia L. Calder, Peter Adamson |
| المصدر: | The Journal of Immunology. 198:1093-1103 |
| بيانات النشر: | The American Association of Immunologists, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | Receptors, CCR6, 0301 basic medicine, Adoptive cell transfer, Chromosomal Proteins, Non-Histone, Immunology, Down-Regulation, chemical and pharmacologic phenomena, Inflammation, Biology, Retina, Autoimmune Diseases, Uveitis, Mice, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, In vivo, medicine, Animals, Immunology and Allergy, Secretion, Orphan receptor, Tumor Necrosis Factor-alpha, Nuclear Proteins, Forkhead Transcription Factors, hemic and immune systems, Nuclear Receptor Subfamily 1, Group F, Member 3, Th1 Cells, In vitro, Bromodomain, 030104 developmental biology, Cancer research, Cytokines, Th17 Cells, Female, medicine.symptom, Transcription Factors, 030215 immunology |
| الوصف: | Experimental autoimmune uveitis (EAU), in which CD4+ Th1 and/or Th17 cells are immunopathogenic, mimics various clinical features of noninfectious uveitis in humans. The impact of bromodomain extraterminal (BET) inhibitors on Th17 cell function was studied in a mouse model of EAU in vivo and in mouse and human Th17 cells in vitro. Two BET inhibitors (GSK151 and JQ1) were able to ameliorate the progression of inflammation in EAU and in mouse CD4+ T cells in vitro, downregulating levels of Th17 cells. Additionally, the uveitogenic capacity of Th17 cells to transfer EAU was abrogated by BET inhibitors in an adoptive transfer model. In human CD4+ T cells, a 5-d exposure to BET inhibitors was accompanied by a significant downregulation of Th17-associated genes IL-17A, IL-22, and retinoic acid–related orphan receptor γt. However, in vitro, the inhibitors had no effect on already polarized Th17 cells. The key finding is that, in response to BET inhibitors, Th17-enriched cultures developed a regulatory phenotype, upregulated FOXP3 expression and IL-10 secretion, and lost pathogenicity in vivo. We conclude that BET targeting of Th17 cells is a potential therapeutic opportunity for a wide range of inflammatory and autoimmune diseases, including uveitis. |
| تدمد: | 1550-6606 0022-1767 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::563d25efcfa6940610ea43d4af1f068fTest https://doi.org/10.4049/jimmunol.1600735Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....563d25efcfa6940610ea43d4af1f068f |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15506606 00221767 |
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