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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 TNF?-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 TNF?-activated intracellular signaling. Collectively, these findings demonstrate that PGRN is a ligand of TNFR, an antagonist of TNF? signaling, and plays a critical role in the pathogenesis of inflammatory arthritis in mice. They also suggest new potential therapeutic interventions for various TNF?-mediated pathologies and conditions, including rheumatoid arthritis.

SUBMITTER: Tang W

PROVIDER: S-EPMC3104397 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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

Tang Wei W Lu Yi Y Tian Qing-Yun QY Zhang Yan Y Guo Feng-Jin FJ Liu Guang-Yi GY Syed Nabeel Muzaffar NM Lai Yongjie Y Lin Edward Alan EA Kong Li L Su Jeffrey J Yin Fangfang F Ding Ai-Hao AH Zanin-Zhorov Alexandra A Dustin Michael L ML Tao Jian J Craft Joseph J Yin Zhinan Z Feng Jian Q JQ Abramson Steven B SB Yu Xiu-Ping XP Liu Chuan-ju CJ

Science (New York, N.Y.) 20110310 6028

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 selecti ...[more]

PMID: 21393509

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Project description:ObjectiveTumour necrosis factor alpha (TNF-α) signalling plays a central role in the pathogenesis of various autoimmune diseases, particularly inflammatory arthritis. This study aimed to repurpose clinically approved drugs as potential inhibitors of TNF-α signalling in treatment of inflammatory arthritis.MethodsIn vitro and in vivo screening of an Food and Drug Administration (FDA)-approved drug library; in vitro and in vivo assays for examining the blockade of TNF actions by fexofenadine: assays for defining the anti-inflammatory activity of fexofenadine using TNF-α transgenic (TNF-tg) mice and collagen-induced arthritis in DBA/1 mice. Identification and characterisation of the binding of fexofenadine to cytosolic phospholipase A2 (cPLA2) using drug affinity responsive target stability assay, proteomics, cellular thermal shift assay, information field dynamics and molecular dynamics; various assays for examining fexofenadine inhibition of cPLA2 as well as the dependence of fexofenadine's anti-TNF activity on cPLA2.ResultsSerial screenings of a library composed of FDA-approved drugs led to the identification of fexofenadine as an inhibitor of TNF-α signalling. Fexofenadine potently inhibited TNF/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ĸB) signalling in vitro and in vivo, and ameliorated disease symptoms in inflammatory arthritis models. cPLA2 was isolated as a novel target of fexofenadine. Fexofenadine blocked TNF-stimulated cPLA2 activity and arachidonic acid production through binding to catalytic domain 2 of cPLA2 and inhibition of its phosphorylation on Ser-505. Further, deletion of cPLA2 abolished fexofenadine's anti-TNF activity.ConclusionCollectively, these findings not only provide new insights into the understanding of fexofenadine action and underlying mechanisms but also provide new therapeutic interventions for various TNF-α and cPLA2-associated pathologies and conditions, particularly inflammatory rheumatic diseases.

Dataset Information

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

Publications

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

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