TNF/TNFR: a gold mine for therapeutic tools

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Many studies of TNF-α have demonstrated its pivotal role in fueling inflammation, a multistep process that promotes autoimmunity (e.g., rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, psoriasis, and refractory asthma) and cancer. Many TNF inhibitors, such as neutralizing monoclonal antibodies (mAbs) (e.g., infliximab, adalimumab, and golimumab) have been developed to treat these chronic inflammatory disorders, demonstrating that altering ligand/receptor interactions with neutralizing mAbs is an invaluable strategy for treating certain chronic inflammatory disorders. Other TNF-α antagonists, such as etanercept, a TNFR2-immunoglobulin Fc fusion protein, can improve the clinical course of rheumatoid arthritis [44].

A large and growing body of evidence has contributed to elucidation of the molecular mechanisms underlying induction of apoptotic and non-apoptotic signaling pathways by TNFR1, and also provided clues regarding how the receptor can switch from one signal to the other. However, the mechanistic links involved in implementation of non-apoptotic signaling pathways by CD95 remain elusive. However, several recent findings have revealed its pro-inflammatory effects [45-51].