Tumor Necrosis Factor (TNF)—α—Induced Interleukin-8 in Human Blood Cultures Discriminates Neutralization by the p55 and p75 TNF Soluble Receptors

• Published in: The Journal of infectious diseases 2000-12, Vol.182 (6), p.1722-1730
• Main Authors: Frishman, Jordan I., Edwards, Carl K., Sonnenberg, Michael G., Kohno, Tadahiko, Cohen, Arthur M., Dinarello, Charles A.
• Format: Article
• Language: English
• Subjects: Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antigens, CD - immunology; Biological and medical sciences; Blood; Blood Cells - drug effects; Blood Cells - immunology; Cells, Cultured; Cytokines; Dose-Response Relationship, Drug; Human viral diseases; Humans; Infectious diseases; Interleukin 1 Receptor Antagonist Protein; Interleukin-8 - analysis; Interleukin-8 - immunology; Interleukins; Ligands; Major Articles; Medical sciences; Mortality; Neutralization Tests; Pharmacology. Drug treatments; Polyethylene Glycols; Receptors; Receptors, Tumor Necrosis Factor - immunology; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor, Type II; Recombinant Fusion Proteins - immunology; Sepsis; Sialoglycoproteins - analysis; Sialoglycoproteins - immunology; Trimers; Tumor necrosis factor receptors; Tumor Necrosis Factor-alpha - pharmacology; Tumor necrosis factors; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1086/317605

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-α—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-α—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-α—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-α 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.