title: TNFα triggers release of extracellular vesicles containing TNFR1 and TRADD, which can modulate TNFα responses of the parental cells.
abstract: Tumor necrosis factor-α (TNFα)-induced reactions are effective to maintain homeostasis; however, excessive responses play progressive roles in the pathogenesis of various chronic inflammatory diseases. We demonstrate that TNFα triggered the release of its receptor TNFR1 as a content of extracellular vesicles (EVs) from the human bronchial epithelial cell, BEAS-2b. The TNFR1 cytoplasmic domain binding partner, TNFR-associated death domain (TRADD), was released by TNFα treatment along with TNFR1. TNFα-triggered release of EVs was decreased in the presence of amitriptyline, an inhibitor of acid sphingomyelinase (A-SMase), or of GW4869, an inhibitor of neutral sphingomyelinase (N-SMase), indicating that EVs containing TNFR1 and TRADD are released through A-SMase and N-SMase dependent manners. From sucrose density gradient analysis, each sphingomyelinase is involved in the generation of distinct populations of EVs. Inhibition of A-SMase or N-SMase resulted in significantly increased responses to TNFα in parental cells. Given that TRADD serves as a platform for the assembly of subsequent signaling molecules, the TNFα triggered release of TNFR1 and TRADD might be an effective strategy for down regulation of the TNFα responses of parental cells.
authors.affiliation: Division of Oral Biochemistry, Niigata University Graduate School of Medical and Dental Sciences, 2-5274 Gakkocho-dori, Chuo-ku, Niigata 951-8514, Japan. Electronic address: sohda@dent.niigata-u.ac.jp.
authors.forename: Miwa
authors.initials: M
authors.lastname: Sohda
authors.affiliation: Department of Cell Biology, Fukuoka University School of Medicine, Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Misumi
authors.affiliation: Division of Oral Biochemistry, Niigata University Graduate School of Medical and Dental Sciences, 2-5274 Gakkocho-dori, Chuo-ku, Niigata 951-8514, Japan.
authors.forename: Kimimitsu
authors.initials: K
authors.lastname: Oda
mesh_terms: D001980:Bronchi / Q000166:cytology / Q000378:metabolism; D002460:Cell Line; D000067128:Extracellular Vesicles / Q000378:metabolism*; D006801:Humans; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000166:cytology* / Q000378:metabolism; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D053199:TNF Receptor-Associated Death Domain Protein / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D047888:Receptors, Tumor Necrosis Factor, Type I; D053199:TNF Receptor-Associated Death Domain Protein; D014409:Tumor Necrosis Factor-alpha; D013108:Sphingomyelin Phosphodiesterase
keywords: Extracellular vesicles; TNFR1; TNFα; TRADD