Rheumatoid arthritis, a persistent autoimmune condition primarily impacting the joints, results in discomfort, rigidity, and inflammation. This disease transpires when the immune system erroneously targets the body’s own tissues, leading to inflammation and joint damage, as well as affecting other organs. At Osaka University (OU), researchers have identified a protein complex that is instrumental in the development of rheumatoid arthritis. Importantly, their research has shown that celastrol, a compound in a medicinal herb, can effectively thwart the disease’s progression by inhibiting this protein complex.
A potent immune system is generally advantageous, yet there are circumstances where it malfunctions and turns against the body. This occurrence, known as autoimmunity, underpins various disorders such as rheumatoid arthritis, Crohn’s disease, type 1 diabetes, and celiac disease. To counteract these conditions, comprehending the initiating mechanisms is crucial.
Recently, Science Immunology published a study from an OU research team that has made significant strides towards this goal. They have discovered a protein complex, made up of COMMD3 and COMMD8, which speeds up rheumatoid arthritis. Furthermore, they’ve found that celastrol, a compound derived from the medicinal plant known as “Thunder God vine”, inhibits the COMMD3/8 complex effectively.
The team’s previous work showed that the COMMD3/8 complex enhances the humoral immune response, although its role in autoimmune diseases remained uncertain. By developing a mouse model with switchable COMMD3 expression, the researchers showed that the elimination of COMMD3 results in the degradation of COMMD8 and consequently, the removal of the COMMD3/8 complex.
Without the COMMD3/8 complex, the humoral immune response was impaired. This led to a decrease in cells producing antibodies, which suggests that the COMMD3/8 complex plays a vital part in the autoimmune response.
The researchers then used a mouse model of rheumatoid arthritis, suppressing COMMD3 expression when the mice began showing initial symptoms. As a result, disease progression halted, indicating the role of the COMMD3/8 complex in promoting autoimmunity.
After determining the importance of the COMMD3/8 complex in autoimmunity, the researchers focused on finding a compound that could disrupt the complex’s formation. Their search led to celastrol, the most potent inhibitor of the COMMD3/8 complex.
Celastrol, an active compound from Tripterygium wilfordii, is known for its anti-inflammatory properties. The study demonstrated that celastrol binds to COMMD3, preventing the formation of the COMMD3/8 complex, which hampers the antibody response and impedes the progression of rheumatoid arthritis in the mouse model.
As the COMMD3/8 complex plays a critical role in the development of rheumatoid arthritis and other autoimmune conditions, it offers a promising therapeutic target. The discovery of celastrol’s inhibitory effects makes it an exciting prospect for developing future treatments for rheumatoid arthritis and other autoimmune diseases.
The study was funded by several organizations including the Japan Society for the Promotion of Science, the Japan Agency for Medical Research and Development, the Japan Science and Technology Agency, the Takeda Science Foundation, the KANAE Foundation, and Chugai Pharmaceutical Co., Ltd.
