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.