title: Tumor necrosis factor (TNF)-alpha-induced interleukin-8 in human blood cultures discriminates neutralization by the p55 and p75 TNF soluble receptors.
abstract: The dose-dependent increase in mortality in patients with sepsis who are treated with tumor necrosis factor (TNF) p75 soluble receptor Fc conjugate (p75-Fc) remains unexplained. In this study, neutralization of TNF-alpha-induced interleukin (IL)-8 by p75-Fc in whole human blood exhibited a U-shaped inhibition curve, whereas the TNF-soluble p55 receptor, linked to polyethylene glycol (p55-PEG), exhibited a dose-dependent inhibition. Native soluble p75 increased TNF-alpha-induced IL-8, versus a 61% reduction by native p55. Spontaneous IL-8 production was increased by p75-Fc or native p75 but not by p55-PEG or native p55. Unexpectedly, TNF-alpha-stimulated IL-1 receptor antagonist was suppressed by p75-Fc but not by p55-PEG. Studies of binding to TNF trimer revealed that p75-Fc has an affinity 40-fold lower than that of p55-PEG and a faster off rate. Native and p75-Fc pass TNF-alpha to membrane receptors more readily than does native or p55-PEG, which may partly explain the increased mortality in patients with sepsis who are treated with p75-Fc.
authors.affiliation: Department of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
authors.forename: J I
authors.initials: JI
authors.lastname: Frishman
authors.forename: C K
authors.initials: CK
authors.lastname: Edwards
authors.forename: M G
authors.initials: MG
authors.lastname: Sonnenberg
authors.forename: T
authors.initials: T
authors.lastname: Kohno
authors.forename: A M
authors.initials: AM
authors.lastname: Cohen
authors.forename: C A
authors.initials: CA
authors.lastname: Dinarello
mesh_terms: D015703:Antigens, CD / Q000276:immunology*; D001773:Blood Cells / Q000187:drug effects* / Q000276:immunology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D016209:Interleukin-8 / Q000032:analysis / Q000276:immunology*; D009500:Neutralization Tests; D011092:Polyethylene Glycols; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D011993:Recombinant Fusion Proteins / Q000276:immunology; D012795:Sialoglycoproteins / Q000032:analysis / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D015703:Antigens, CD; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D016209:Interleukin-8; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D011993:Recombinant Fusion Proteins; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha; D011092:Polyethylene Glycols