LIPOPOLYSACCHARIDE LPS-MEDIATED SOLUBLE TNF RECEPTOR RELEASE AND TNF RECEPTOR EXPRESSION BY MONOCYTES - ROLE OF CD14, LPS BINDING-PROTEIN, AND BACTERICIDAL PERMEABILITY-INCREASING PROTEIN/

Previously we demonstrated that two soluble (s) tumor necrosis factor receptors, TNF-R55 as well as sTNF-R75, are constitutively released in vitro by monocytes, and that this release was markedly enhanced after activation. Because LPS is an important activator of monocytes, we in vestigated the effect of LPS on sTNF-R release by monocytes. It was fo und that release of sTNF-R75, but not (or minimally) release of sTNF-R 55, was enhanced after activation with LPS, reaching plateau levels af ter approximately 2 days. CD14, one of the membrane receptors for LPS, is an intermediate in this process, as shown in experiments using mAb directed against CD14. Under serum-free conditions, LPS-induced sTNF- R75 release was less as compared with release in the presence of serum , suggesting involvement of serum proteins. Addition of LPS binding pr otein (LBP) enhanced the LPS-induced sTNF-R75 release under serum-free conditions, but had no effect in the presence of serum. On the other hand, bactericidal/permeability-increasing protein (BPI), known to pos sess LPS neutralizing activity, inhibited LPS-induced sTNF-R75 release . Furthermore, cell surface expression of both types of TNF-R was show n to be controlled by LPS, LBP, and BPI. LPS caused, within 1 h, a com plete reduction of TNF-R55 as well as TNF-R75 expression, followed by enhanced re-expression of both receptors after 24 h. The down-modulati on of expression was increased by LBP, whereas BPI counteracted the LP S-induced down-regulation. The LPS-enhanced release of sTNF-R75, capab le of inactivation of TNF, as well as LPS-induced initial down-modulat ion of TNF-R expression leading to postulated temporary unresponsivene ss to TNF may share in a physiological mechanism to carefully control the effects of TNF.