title: Immunomodulatory drugs inhibit TLR4-induced type-1 interferon production independently of Cereblon via suppression of the TRIF/IRF3 pathway.
abstract: 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.
authors: Laboratory of Immune Regulation, IFReC Research Building, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: David
authors: D
authors: Millrine
authors: Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
authors: Haruhiko
authors: H
authors: Miyata
authors: Laboratory of Immune Regulation, IFReC Research Building, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Mami
authors: M
authors: Tei
authors: Laboratory of Immune Regulation, IFReC Research Building, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Praveen
authors: P
authors: Dubey
authors: Laboratory of Immune Regulation, IFReC Research Building, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Kishan
authors: K
authors: Nyati
authors: Laboratory of Immune Regulation, IFReC Research Building, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Taisuke
authors: T
authors: Nakahama
authors: Laboratory of Immune Regulation, IFReC Research Building, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Yohannes
authors: Y
authors: Gemechu
authors: Laboratory of Immune Regulation, IFReC Research Building, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Barry
authors: B
authors: Ripley
authors: Laboratory of Immune Regulation, IFReC Research Building, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan kishimoto@ifrec.osaka-u.ac.jp.
authors: Tadamitsu
authors: T
authors: Kishimoto
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D064112:Clustered Regularly Interspaced Short Palindromic Repeats; D007155:Immunologic Factors / Q000627:therapeutic use*; D007165:Immunosuppression Therapy; D007249:Inflammation / Q000188:drug therapy*; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D007370:Interferon Type I / Q000378:metabolism; D000077269:Lenalidomide; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D007155:Immunologic Factors; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D000077269:Lenalidomide; D009419:Nerve Tissue Proteins; D013792:Thalidomide; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C549921:Crbn protein, mouse; C494233:Irf3 protein, mouse; C476286:Ticam1 protein, mouse; C493487:Tlr4 protein, mouse; C467566:pomalidomide
keywords: Cereblon; IMiD; innate immunity; thalidomide