Tumor necrosis factor (TNF)-dependent shedding of the p55 TNF receptor in a baboon model of bacteremia

Abstract

We have tested the hypothesis that the tumor necrosis factor (TNF) plays a significant role in vivo in TNF receptor shedding and studied the release of TNF-binding protein 1 (TNF-BP1), the soluble fragment of the 55- to 60-kDa TNF alpha (TNF) receptor, in a baboon model of Escherichia coli bacteremia, using three different doses of bacteria in acute infection (8 h) experiments (n [animals] = 11) and a single dose in a subchronic infection (72 h) experiment. In the subchronic infection study, one group of animals (n = 6) was pretreated with a neutralizing murine monoclonal antibody to TNF (CB0006). Concentrations of TNF and TNF-BP1 in plasma were determined in specific, monoclonal antibody-based immunoassays. Untreated animals (n = 6) showed undetectable TNF concentrations (< 10 pg/ml at baseline), whereas TNF-BP1 levels in plasma were in the range of 2 ng/ml, similar to concentrations observed in humans. Infusion of bacteria resulted in a rapid, dose-dependent increase in plasma TNF concentrations that reached a maximal level after 2 h and returned to baseline within 6 h. TNF-BP1 concentrations also showed a dose-dependent increase to peak concentrations three- to fivefold above baseline within 2 h but, in contrast to TNF levels, remained significantly elevated for up to 48 h. In animals pretreated with antibody CB0006, circulating TNF was completely neutralized, and TNF-BP1 was significantly reduced. We conclude that TNF-BP1 is released in bacteremia and that release in vivo is partially dependent on the presence of TNF.