ANTAGONISTIC EFFECTS OF LIPOPOLYSACCHARIDE-BINDING PROTEIN AND BACTERICIDAL PERMEABILITY-INCREASING PROTEIN ON LIPOPOLYSACCHARIDE-INDUCED CYTOKINE RELEASE BY MONONUCLEAR PHAGOCYTES - COMPETITION FOR BINDING TOLIPOPOLYSACCHARIDE

Serum proteins play an important role in LPS-induced cell activation. The LPS binding protein (LBP) enhances cellular responses to LPS, wher eas the polymorphonuclear leukocyte product bactericidal/permeability- increasing protein (BPI) inhibits LPS-induced cell activation. In this study the influences of LBP and BPI, two proteins with opposite effec ts, but with considerable sequence homology, on LPS-induced mononuclea r phagocytic cell cytokine release was studied. LBP was shown to enhan ce LPS-induced TNF-alpha, IL-6, and IL-8 release by mononuclear phagoc ytic cells, whereas BPI inhibited the release of these cytokines. Furt hermore, the effects of LBP and BPI on LPS-induced cytokine release by mononuclear phagocytic cells were shown to be counteractive. BPI inte rfered with the enhancing effect of LBP on the LPS-induced cytokine re lease. At high LBP to BPI ratios, BPI could no longer inhibit LBP-indu ced enhancement. In accordance, increasing concentrations of BPI abrog ated the LBP effect. Next, it was shown that LBP and BPI compete for b inding to LPS by using an assay system that detects binding of free BP I to an anti-BPI mAb. LPS prevented binding of BPI to anti-BPI mAb, wh ereas preincubation of LPS with LBP prevented the LPS-induced inhibiti on. Also, it was observed that both BPI and LBP inhibited LPS activity in the chromogenic LAL assay. We conclude from this study that LBP an d BPI have counteractive effects on LPS-induced mononuclear phagocytic cell cytokine release by competing for binding to LPS.