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PGRN was previously reported to bind to TNF receptors (TNFR) and is therapeutic against inflammatory arthritis. Here we present further evidences demonstrating the PGRN inhibition of TNFα binding and activity, and clarifying the distinct mechanisms underlying TNFα inhibition between PGRN and classic TNFα-binding inhibitors. In addition, we present evidences indicating that three TNFR binding domains of PGRN act independently in binding to TNFR. Furthermore, changing the order of three TNFR-binding domains in Atsttrin, an PGRN-derived molecule composed of these TNFR-binding domains, does not affect its anti-inflammatory and anti-TNF activities in both collagen-induced inflammatory arthritis and human TNF-α transgenic mouse model. Taken together, these findings provide the additional molecular basis underlying PGRN/TNFR interaction and PGRN-mediated anti-inflammatory activity in various …