IL-27 blocks RORc expression to inhibit lineage commitment of Th17 cells
| Autor: | Daniel J. Cua, Katia Boniface, Cristina M. Tato, Caroline Diveu, Jason S. Stumhofer, Mandy J. McGeachy, Christopher A. Hunter, Robert A. Kastelein, Barbara Joyce-Shaikh, Yi Chen, Manjiri Sathe, Terrill K. McClanahan, Rene de Waal Malefyt |
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| Rok vydání: | 2009 |
| Předmět: |
Encephalomyelitis
Autoimmune Experimental Receptors Retinoic Acid Encephalomyelitis Immunology Biology Proinflammatory cytokine Mice RAR-related orphan receptor gamma In vivo medicine Immunology and Allergy Animals Humans Cell Lineage Genetic Predisposition to Disease Interleukin 27 Transcription factor Cells Cultured Mice Knockout Receptors Thyroid Hormone Interleukins Experimental autoimmune encephalomyelitis Interleukin-17 Cell Differentiation T-Lymphocytes Helper-Inducer Nuclear Receptor Subfamily 1 Group F Member 3 medicine.disease Growth Inhibitors Mice Inbred C57BL Protein Subunits Gene Expression Regulation Experimental pathology |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950). 182(9) |
| ISSN: | 1550-6606 |
| Popis: | IL-27 is secreted by APCs in response to inflammatory stimuli and exerts a proinflammatory Th1-enhancing activity but also has significant anti-inflammatory functions. We examined the molecular mechanism by which IL-27 regulates TGFβ plus IL-6- or IL-23-dependent Th17 development in the mouse and human systems. IL-27 inhibited the production of IL-17A and IL-17F in naive T cells by suppressing, in a STAT1-dependent manner, the expression of the Th17-specific transcription factor RORγt. The in vivo significance of the role of IL-27 was addressed in delayed-type hypersensitivity response and experimental autoimmune encephalomyelitis (EAE). By generating mice deficient for the p28 subunit of IL-27, we showed that IL-27 regulated the severity of delayed-type hypersensitivity response and EAE through its effects on Th17 cells. Furthermore, up-regulation of IL-10 in the CNS, which usually occurs late after EAE onset and plays a role in the resolution of the disease, was notably absent in IL-27p28−/− mice. These results show that IL-27 acts as a negative regulator of the developing IL-17A response in vivo, suggesting a potential therapeutic role for IL-27 in autoimmune diseases. |
| Databáze: | OpenAIRE |
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