Herbs-Phytochemicals: Celastrol From Tripterygium Wilfordii Inhibits Rheumatoid Arthritis Progression By Targeting The COMMD3/8 Complex
Herbs-Phytochemicals - Celastrol - Arthritis Apr 05, 2023 1 year, 8 months, 2 weeks, 3 days, 10 hours, 31 minutes ago
Herbs-Phytochemicals: The immune system plays a vital role in protecting our bodies from infections and diseases. However, sometimes the immune system malfunctions and attacks the body, resulting in autoimmune disorders such as rheumatoid arthritis, Crohn's disease, type 1 diabetes, and celiac disease.
A recent study by scientists from Laboratory of Immune Response Dynamics, WPI Immunology Frontier Research Center, Osaka University-Japan offers hope in the battle against these diseases by identifying a protein complex that promotes the progression of rheumatoid arthritis and a potent herbal compound that inhibits its function.
The Japanese study team focused on a protein complex comprising two proteins called COMMD3 and COMMD8. The study team had previously demonstrated that the COMMD3/8 complex potentiates the humoral immune response, but its role in autoimmune diseases remained unclear.
In order to investigate further, the study team generated a mouse model in which the expression of COMMD3 could be switched off. Deletion of COMMD3 resulted in the degradation of COMMD8 and the disappearance of the COMMD3/8 complex. This led to an impaired humoral immune response and a decrease in cells producing antibodies, highlighting the importance of the COMMD3/8 complex in autoimmune responses.
Subsequently, utilizing a mouse model of rheumatoid arthritis, the study team repressed COMMD3 expression when the mice exhibited the first symptoms of the disease. This intervention halted the progression of the disease, indicating that the COMMD3/8 complex plays a crucial role in promoting the autoimmune response.
Lead author, Dr Taiichiro Shirai,a professor at the Graduate School of Medicine, Osaka University told
Herbs-Phytochemicals reporters from TMN, "Deleting COMMD3 results in the degradation of COMMD8 and, consequently, the disappearance of the COMMD3/8 complex. The absence of the COMMD3/8 complex led to an impaired humoral immune response. The number of cells producing antibodies decreased, suggesting that the COMMD3/8 complex has an important role in the autoimmune response.”
Having established the importance of the COMMD3/8 complex in autoimmunity, the study team sought to identify a compound that could interfere with its formation. Their chemical screen revealed Celastrol, an extract from the root of a medicinal herb plant called Tripterygium wilfordii (colloquially known as "Thunder God vine"), as the most potent inhibitor of the COMMD3/8 complex.
Celastrol has long been known for its anti-inflammatory properties, but its mechanism of action had not been fully explained.
The study showed that celastrol binds covalently to COMMD3, preventing the formation of the COMMD3/8 complex. This impairs the antibody response and blocks the progression of rheumatoid arthritis in the mouse model.
The discovery of celastrol's mechanism of action is a significant step forward in understanding its potential therapeutic applications.
The study findings establish that celastrol exerts its immunosuppressive activity by targeting the CO
MMD3/8 complex. This suggests that the COMMD3/8 complex could be a promising drug target for autoimmune diseases, with celastrol being a lead pharmacologic candidate for developing treatments against rheumatoid arthritis and other autoimmune conditions.
The identification of the COMMD3/8 complex as a potential drug target in B cell-dependent autoimmune diseases opens new avenues for research and treatment development. Celastrol's ability to disrupt the COMMD3/8 complex and inhibit arthritis progression is a valuable insight into the molecular mechanism behind its anti-arthritic activity. Further research into celastrol and the COMMD3/8 complex could lead to more effective treatments for rheumatoid arthritis and also other autoimmune disorders.
The study findings were published in the peer reviewed journal: Science Immunology.
https://www.science.org/doi/10.1126/sciimmunol.adc9324
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