Immunomodulatory drugs inhibit TLR4-induced type-1 interferon production independently of Cereblon via suppression of the TRIF/IRF3 pathway
| Autor: | Mami Tei, Tadamitsu Kishimoto, Praveen K Dubey, Kishan K. Nyati, Yohannes Gemechu, Haruhiko Miyata, Barry Ripley, Taisuke Nakahama, David Millrine |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
medicine.medical_treatment Immunology Nerve Tissue Proteins Pharmacology Mice 03 medical and health sciences Interferon medicine Animals Immunologic Factors Immunology and Allergy Clustered Regularly Interspaced Short Palindromic Repeats Lenalidomide Cells Cultured Adaptor Proteins Signal Transducing Immunosuppression Therapy Inflammation Mice Knockout Tumor Necrosis Factor-alpha business.industry Macrophages Cereblon General Medicine Thalidomide Mice Inbred C57BL Toll-Like Receptor 4 Adaptor Proteins Vesicular Transport 030104 developmental biology Cytokine TRIF Interferon Type I TLR4 Interferon Regulatory Factor-3 Tumor necrosis factor alpha business IRF3 Signal Transduction medicine.drug |
| Zdroj: | International Immunology. 28:307-315 |
| ISSN: | 1460-2377 0953-8178 |
| DOI: | 10.1093/intimm/dxw005 |
| Popis: | Thalidomide and its derivatives, collectively referred to as immunomodulatory drugs (IMiDs), are effective inhibitors of inflammation and are known to inhibit TLR-induced TNFα production. The identification of Cereblon as the receptor for these compounds has led to a rapid advancement in our understanding of IMiD properties; however, there remain no studies addressing the role of Cereblon in mediating the suppressive effect of IMiDs on TLR responses. Here, we developed Cereblon-deficient mice using the CRISPR-Cas9 system. TLR-induced cytokine responses were unaffected by Cereblon deficiency in vivo. Moreover, IMiD treatment inhibited cytokine production even in the absence of Cereblon. The IMiD-induced suppression of cytokine production therefore occurs independently of Cereblon in mice. Further investigation revealed that IMiDs are potent inhibitors of TLR-induced type-1 interferon production via suppression of the TRIF/IRF3 pathway. These data suggest that IMiDs may prove effective in the treatment of disorders characterized by the ectopic production of type-1 interferon. Significantly, these properties are mediated separately from thalidomide’s teratogenic receptor, Cereblon. Thus, certain therapeutic properties of Thalidomide can be separated from its harmful side effects. |
| Databáze: | OpenAIRE |
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