Suppression of TH17 Differentiation and Autoimmunity by a Synthetic ROR Ligand
| Autor: | Jihong Xu, Stephan C. Schürer, Thomas P. Burris, William R. Roush, P. Naresh Kumar, J. J. Liu, Janelle L. Lauer, Yongjun Wang, Dusica Vidovic, Gail Wagoner, Laura A. Solt, Theodore M. Kamenecka, Patrick R. Griffin, Monica A. Istrate, Paul D. Drew, Philippe Nuhant |
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| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Autoimmune disease
0303 health sciences medicine.medical_specialty Cell type Multidisciplinary Cellular differentiation HEK 293 cells Biology medicine.disease Article 3. Good health Cell biology 03 medical and health sciences 0302 clinical medicine Endocrinology Nuclear receptor RAR-related orphan receptor gamma 030220 oncology & carcinogenesis Internal medicine medicine Interleukin 17 Receptor 030304 developmental biology |
| Zdroj: | Nature |
| ISSN: | 1476-4687 0028-0836 |
| Popis: | T-helper cells that produce interleukin-17 (T(H)17 cells) are a recently identified CD4(+) T-cell subset with characterized pathological roles in autoimmune diseases. The nuclear receptors retinoic-acid-receptor-related orphan receptors α and γt (RORα and RORγt, respectively) have indispensible roles in the development of this cell type. Here we present SR1001, a high-affinity synthetic ligand-the first in a new class of compound-that is specific to both RORα and RORγt and which inhibits T(H)17 cell differentiation and function. SR1001 binds specifically to the ligand-binding domains of RORα and RORγt, inducing a conformational change within the ligand-binding domain that encompasses the repositioning of helix 12 and leads to diminished affinity for co-activators and increased affinity for co-repressors, resulting in suppression of the receptors' transcriptional activity. SR1001 inhibited the development of murine T(H)17 cells, as demonstrated by inhibition of interleukin-17A gene expression and protein production. Furthermore, SR1001 inhibited the expression of cytokines when added to differentiated murine or human T(H)17 cells. Finally, SR1001 effectively suppressed the clinical severity of autoimmune disease in mice. Our data demonstrate the feasibility of targeting the orphan receptors RORα and RORγt to inhibit specifically T(H)17 cell differentiation and function, and indicate that this novel class of compound has potential utility in the treatment of autoimmune diseases. |
| Databáze: | OpenAIRE |
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