title: Identification and characterization of a novel spliced variant that encodes human soluble tumor necrosis factor receptor 2.
abstract: Tumor necrosis factor (TNF)-alpha is a pleiotropic cytokine involved in a broad spectrum of inflammatory and immune responses including proliferation, differentiation and cell death induction in several cell types. The biological effects of TNF-alpha are mediated via the cell-surface TNF receptors TNFR1 and TNFR2. Soluble forms of these two receptors, which contain the extracellular ectodomains, are proteolytically cleaved from the membrane. High levels of soluble (s) TNFR2 in serum have been documented in multiple inflammatory pathologies. We describe here a new differential spliced isoform of human TNFR2 missing exons 7 and 8, DS-TNFR2(Delta7,8). This novel isoform lacks the transmembrane and cytoplasmic domains. Expression studies with DS-TNFR2(Delta7,8) cDNA transiently transfected COS cells showed that it encodes a sTNFR2 receptor of approximately 42 kDa. Soluble DS-TNFR2(Delta7,8) blocked TNF-alpha-induced apoptosis, which suggests that it regulates TNF-alpha function by antagonizing its biological activity. An ELISA was developed that quantifies sTNFR2 generated by alternative splicing. Our data show that sTNFR2 generated by alternative splicing can be found in sera of healthy individuals, at increased levels in patients with sepsis and at high concentrations in rheumatoid arthritis patients.
authors.affiliation: Immunology Unit, Department of Cellular Biology and Pathology, Medical School, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, 08036 Barcelona, Spain.
authors.forename: Begoña
authors.initials: B
authors.lastname: Lainez
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Fernandez-Real
authors.forename: Xavier
authors.initials: X
authors.lastname: Romero
authors.forename: Enric
authors.initials: E
authors.lastname: Esplugues
authors.forename: Juan D
authors.initials: JD
authors.lastname: Cañete
authors.forename: Wifredo
authors.initials: W
authors.lastname: Ricart
authors.forename: Pablo
authors.initials: P
authors.lastname: Engel
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017398:Alternative Splicing; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000235:genetics; D001483:Base Sequence; D019556:COS Cells; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D004797:Enzyme-Linked Immunosorbent Assay; D000068800:Etanercept; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000032:analysis* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020033:Protein Isoforms / Q000235:genetics*; D018124:Receptors, Tumor Necrosis Factor / Q000032:analysis* / Q000235:genetics*; D018805:Sepsis / Q000097:blood / Q000235:genetics; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D007074:Immunoglobulin G; D020033:Protein Isoforms; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept