Immunomodulatory drugs inhibit TLR4-induced type-1 interferon production independently of Cereblon via suppression of the TRIF/IRF3 pathway

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.

Source: International Immunology - May 29, 2016 Category: Allergy & Immunology Authors: Millrine, D., Miyata, H., Tei, M., Dubey, P., Nyati, K., Nakahama, T., Gemechu, Y., Ripley, B., Kishimoto, T. Tags: Original Research Source Type: research