Pharmacologic Inhibition of RORγt Regulates Th17 Signature Gene Expression and Suppresses Cutaneous Inflammation In Vivo
| Autor: | Lisa A. Orband-Miller, Erkan Baloglu, Jianfei Yang, Ashley A. Barnes, Jill Skepner, Thaddeus J. Carlson, Darby Schmidt, Mark S. Sundrud, Shomir Ghosh, Mercedes Lobera, Jonathan Hill, Radha Ramesh, Mohamed Boudjelal, Mark Trocha |
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| Rok vydání: | 2014 |
| Předmět: |
Adult
CD4-Positive T-Lymphocytes Cellular differentiation Immunology Dermatitis Biology Heterocyclic Compounds 4 or More Rings Jurkat cells Small Molecule Libraries Interleukin 22 Jurkat Cells Mice Fluorescence Resonance Energy Transfer Interleukin 23 Animals Humans Psoriasis Immunology and Allergy Cells Cultured Oligonucleotide Array Sequence Analysis Skin Mice Inbred BALB C Dose-Response Relationship Drug Molecular Structure Reverse Transcriptase Polymerase Chain Reaction Interleukin-17 HEK 293 cells Cell Differentiation Nuclear Receptor Subfamily 1 Group F Member 3 HEK293 Cells Leukocytes Mononuclear Cancer research Th17 Cells Female Interleukin 17 IL17A Transcriptome CD8 |
| Zdroj: | The Journal of Immunology. 192:2564-2575 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | IL-17–producing CD4+Th17 cells, CD8+Tc17 cells, and γδ T cells play critical roles in the pathogenesis of autoimmune psoriasis. RORγt is required for the differentiation of Th17 cells and expression of IL-17. In this article, we describe a novel, potent, and selective RORγt inverse agonist (TMP778), and its inactive diastereomer (TMP776). This chemistry, for the first time to our knowledge, provides a unique and powerful set of tools to probe RORγt-dependent functions. TMP778, but not TMP776, blocked human Th17 and Tc17 cell differentiation and also acutely modulated IL-17A production and inflammatory Th17-signature gene expression (Il17a, Il17f, Il22, Il26, Ccr6, and Il23) in mature human Th17 effector/memory T cells. In addition, TMP778, but not TMP776, inhibited IL-17A production in both human and mouse γδ T cells. IL-23–induced IL-17A production was also blocked by TMP778 treatment. In vivo targeting of RORγt in mice via TMP778 administration reduced imiquimod-induced psoriasis-like cutaneous inflammation. Further, TMP778 selectively regulated Th17-signature gene expression in mononuclear cells isolated from both the blood and affected skin of psoriasis patients. In summary, to our knowledge, we are the first to demonstrate that RORγt inverse agonists: 1) inhibit Tc17 cell differentiation, as well as IL-17 production by γδ T cells and CD8+ Tc17 cells; 2) block imiquimod-induced cutaneous inflammation; 3) inhibit Th17 signature gene expression by cells isolated from psoriatic patient samples; and 4) block IL-23–induced IL-17A expression. Thus, RORγt is a tractable drug target for the treatment of cutaneous inflammatory disorders, which may afford additional therapeutic benefit over existing modalities that target only IL-17A. |
| Databáze: | OpenAIRE |
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