Abstract

Tumor necrosis factor-a (TNFa) has received the greatest attention because of its position at the apex of the pro-inflammatory cytokine cascade, and its dominance in the pathogenesis of inflammation. Anti-TNF therapies have been accepted as the effective approach to treating rheumatoid arthritis. In a global screen for the binding proteins of progranulin (PGRN), an autocrine growth factor with multiple functions, we found that PGRN bound to TNFR1 and TNFR2. PGRN-deficient mice were susceptible to collagen-induced arthritis, and administration of PGRN reversed inflammatory arthritis. More importantly, Atsttrin, an engineered protein composed of three PGRN fragments, exhibited potent anti-inflammatory activity, which surpassed PGRN itself, in vivo. This talk will focus on the interplay between PGRN and TNF in inflammatory arthritis as well as the immunological mechanism involved. The talk will also highlight Atsttrin. Identification of PGRN as a ligand of TNFR and an antagonist of TNFα signaling not only betters our understanding of the pathogenesis of inflammatory arthritis, but also provides new therapeutic interventions for various TNFα-mediated pathologies and conditions, including rheumatoid arthritis.