The growth factor progranulin binds to TNF receptors and is therapeutic against inflammatory arthritis in mice.

Abstract

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.

• Authors: Wei Tang, Yi Lu, Qing-Yun Tian, Yan Zhang, Feng-Jin Guo, Guang-Yi Liu, Nabeel Muzaffar Syed, Yongjie Lai, Edward Alan Lin, Li Kong, Jeffrey Su, Fangfang Yin, Ai-Hao Ding, Alexandra Zanin-Zhorov, Michael L Dustin, Jian Tao, Joseph Craft, Zhinan Yin, Jian Q Feng, Steven B Abramson, Xiu-Ping Yu, Chuan-ju Liu
• Journal: Science (New York, N.Y.) (Science) Vol. 332 Issue 6028 Pg. 478-84 (Apr 22 2011) ISSN: 1095-9203 [Electronic] United States
• PMID: 21393509 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Atsttrin fusion protein
• GRN protein, human
• Granulins
• Grn protein, mouse
• Intercellular Signaling Peptides and Proteins
• Ligands
• Progranulins
• Receptors, Tumor Necrosis Factor, Type I
• Receptors, Tumor Necrosis Factor, Type II
• Recombinant Fusion Proteins
• Recombinant Proteins
• TNFRSF1A protein, human
• TNFRSF1B protein, human
• Tumor Necrosis Factor-alpha

Topics

• Adolescent
• Adult
• Aged
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (metabolism, pharmacology, therapeutic use)
• Arthritis, Experimental (drug therapy, immunology, pathology, physiopathology)
• Cartilage, Articular (metabolism, pathology)
• Female
• Granulins
• Humans
• Intercellular Signaling Peptides and Proteins (chemistry, genetics, metabolism, therapeutic use)
• Ligands
• Male
• Mice
• Mice, Inbred Strains
• Mice, Knockout
• Mice, Transgenic
• Middle Aged
• Progranulins
• Protein Interaction Domains and Motifs
• Receptors, Tumor Necrosis Factor, Type I (genetics, metabolism)
• Receptors, Tumor Necrosis Factor, Type II (genetics, metabolism)
• Recombinant Fusion Proteins (metabolism, pharmacology, therapeutic use)
• Recombinant Proteins (therapeutic use)
• Signal Transduction
• T-Lymphocytes, Regulatory (immunology, physiology)
• Tumor Necrosis Factor-alpha (metabolism)
• Young Adult