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The activation of TNF-α/NF-кB signaling is involved in the regulation of a wide range of biological processes, such as cell proliferation, differentiation and apoptosis, eventually causing a number of diseases, such as cancer and inflammation. Here, we found that TNF-α/NF-кB signaling was activated in a large number of blood samples taken from foot and ankle rheumatoid arthritis (RA) patients. By applying a microarray assay to the human synovial sarcoma cell line SW982 and the human fibroblast-like synoviocyte cell line HFLS-RA, as well as in their corresponding p65 knockdown and -overexpressing cells, we identified and verified the activation of many p65 targets, including cytokines (e.g., TNF-α and IL-6 ), chemokines (e.g., MCP-1 and PANTES ), protein receptors (e.g., CD-40 and MHC-1 ), and inducible enzymes (e.g., COX2 ). In addition, we subjected microRNAs from foot and ankle RA patients to a microRNA-specific microarray and found that miR-7-5p targeted the 3'-UTR of p65 , negatively regulating its expression. By applying an in vitro screen to identify small molecules that specifically inhibited the interaction between TRADD and TNFR2, we found that NSM00191 strongly inhibited the activation of TNF-α/NF-кB signaling in vitro and in vivo , causing the downregulation of NF-кB targets and the decrease of arthritis scores. Collectively, our findings shed new light on the regulation of the TNF-α/NF-кB axis and might provide a new avenue for RA treatment.

The small molecule NSM00191 specifically represses the TNF-α/NF-кB axis in foot and ankle rheumatoid arthritis