Novel small molecule IL-6 inhibitor suppresses autoreactive Th17 development and promotes Treg development
| Autor: | Emma E. Kraus, Nivedita Jena, Chenglong Li, Marissa C. Granitto, Marissa F. Farinas, Amy E. Lovett-Racke, E Y Zhao, Wei Pei, G Perottino, James R. Fuchs, Michael K. Racke, S I Aqel, V Kumari, Yuhong Yang, L Mao |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Adoptive cell transfer biology Chemistry Effector Immunology Experimental autoimmune encephalomyelitis Interleukin medicine.disease In vitro 03 medical and health sciences 030104 developmental biology 0302 clinical medicine STAT protein biology.protein Cancer research medicine Immunology and Allergy Signal transduction Interleukin 6 030215 immunology |
| Zdroj: | Clinical and Experimental Immunology. 196:215-225 |
| ISSN: | 1365-2249 0009-9104 |
| Popis: | Summary Multiple sclerosis (MS) is the leading cause of non-traumatic neurological disability in the United States in young adults, but current treatments are only partially effective, making it necessary to develop new, innovative therapeutic strategies. Myelin-specific interleukin (IL)-17-producing T helper type 17 (Th17) cells are a major subset of CD4 T effector cells (Teff) that play a critical role in mediating the development and progression of MS and its mouse model, experimental autoimmune encephalomyelitis (EAE), while regulatory T cells (Treg) CD4 T cells are beneficial for suppressing disease. The IL-6/signal transducer and activator of transcription 3 (STAT-3) signaling pathway is a key regulator of Th17 and Treg cells by promoting Th17 development and suppressing Treg development. Here we show that three novel small molecule IL-6 inhibitors, madindoline-5 (MDL-5), MDL-16 and MDL-101, significantly suppress IL-17 production in myelin-specific CD4 T cells in a dose-dependent manner in vitro. MDL-101 showed superior potency in suppressing IL-17 production compared to MDL-5 and MDL-16. Treatment of myelin-specific CD4 T cells with MDL-101 in vitro reduced their encephalitogenic potential following their subsequent adoptive transfer. Furthermore, MDL-101 significantly suppressed proliferation and IL-17 production of anti-CD3-activated effector/memory CD45RO+CD4+ human CD4 T cells and promoted human Treg development. Together, these data demonstrate that these novel small molecule IL-6 inhibitors have the potential to shift the Teff : Treg balance, which may provide a novel therapeutic strategy for ameliorating disease progression in MS. |
| Databáze: | OpenAIRE |
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