A research group of Tadamitsu Kishimoto (Immune Regulation, IFReC) revealed an inhibitory mechanism of thalidomide on inflammatory immune responses. It is known that the drug thalidomide binds to Cereblon protein, thereby performing an anti-tumor effect on myeloma cells. In addition, thalidomide also have an inhibitory effect on production of inflammatory cytokines such as TNF-α, IL-6 and interferon. In this study, they showed that the drug thalidomide releases Rabex5, which is known as an inhibitor of inflammatory cytokine productions, from it binding to Cereblon, which enabled Rabex5 to work as a suppressor of inflammatory immune responses. This study will give a hint of how thalidomide is efficacious on autoimmune inflammatory disease such as rheumatoid arthritis.

Abstract

Immunomodulatory drugs (IMiDs) are a family of compounds derived from thalidomide. Binding of the IMiD molecule to the Lon protease Cereblon initiates the degradation of substrates via the ubiquitin proteasome pathway. Here, we show that Cereblon forms a complex with Rabex-5, a regulator of immune homeostasis. Treatment with lenalidomide prevented the association of Cereblon with Rabex-5. Conversely, mutation of the IMiD binding site increased Cereblon–Rabex-5 coimmunoprecipitation. The thalidomide binding region of Cereblon therefore regulates the formation of this complex. Knockdown of Rabex-5 in the THP-1 macrophage cell line up-regulated Toll-like receptor (TLR)-induced cytokine and type 1 IFN production via a STAT1/IRF activating pathway. Thus, we identify Rabex-5 as a IMiD target molecule that functions to restrain TLR activated auto-immune promoting pathways. We propose that release of Rabex-5 from complex with Cereblon enables the suppression of immune responses, contributing to the antiinflammatory properties of IMiDs.

Related link

• World Premier International Research Center, Immunology Frontier Center, Osaka University