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The growth factor progranulin (PGRN) has been implicated in embryonic development, tissue repair, tumorigenesis, and inflammation, but its receptors remain unidentified. We report that PGRN bound directly to tumor necrosis factor receptors (TNFRs) and disturbed the TNFα-TNFR interaction. PGRN-deficient mice were susceptible to collagen-induced arthritis, and administration of PGRN reversed inflammatory arthritis. Atsttrin, an engineered protein composed of three PGRN fragments, exhibited selective TNFR binding. PGRN and Atsttrin prevented inflammation in multiple arthritis mouse models and inhibited TNFα-activated intracellular signaling. Collectively, these findings demonstrate that PGRN is a ligand of TNFR, an antagonist of TNFα signaling, and plays a critical role in the pathogenesis of inflammatory arthritis in mice. They also suggest new potential therapeutic interventions for various TNFα-mediated pathologies and conditions, including rheumatoid arthritis.

Original publication

DOI

10.1126/science.1199214

Type

Journal article

Journal

Science

Publication Date

22/04/2011

Volume

332

Pages

478 - 484

Keywords

Adolescent, Adult, Aged, Animals, Anti-Inflammatory Agents, Non-Steroidal, Arthritis, Experimental, Cartilage, Articular, Female, Humans, Intercellular Signaling Peptides and Proteins, Ligands, Male, Mice, Mice, Inbred Strains, Mice, Knockout, Mice, Transgenic, Middle Aged, Protein Interaction Domains and Motifs, Receptors, Tumor Necrosis Factor, Type I, Receptors, Tumor Necrosis Factor, Type II, Recombinant Fusion Proteins, Recombinant Proteins, Signal Transduction, T-Lymphocytes, Regulatory, Tumor Necrosis Factor-alpha, Young Adult