DUAL EFFECTS OF LPS ANTIBODIES ON CELLULAR UPTAKE OF LPS AND LPS-INDUCED PROINFLAMMATORY FUNCTIONS

Human phagocytes recognize bacterial LPS (endotoxin) through membrane CD14 (mCD14), a proinflammatory LPS receptor, This study tested the hy pothesis that anti-LPS Abs neutralize endotoxin by blocking cellular u ptake through mCD14, Ab-associated changes in the uptake and cellular distribution of FITC-LPS were assessed by flow cytometry and laser sca nning confocal microscopy in human CD14-transfected Chinese hamster ov ary fibroblasts (CHO-CD14 cells) and human peripheral blood monocytes, LPS core- and O-side chain-specific mAbs inhibited mCD14-mediated LPS uptake by both cell types in the presence of serum, O-side chain-spec ific mAb concurrently enhanced complement-dependent LPS uptake by mono cytes through complement receptor-1 (CR1) and uptake by CHO-CD14 cells involving another heat-labile serum factor(s) and cell-associated rec ognition molecule(s), Core-specific mAb inhibited mCD14-mediated uptak e of homologous and heterologous LPS, while producing less concurrent enhancement of non-mCD14-mediated LPS uptake, The modulation by anti-L PS mAbs of mCD14-mediated LPS uptake was associated with inhibition of LPS-induced nuclear factor-kappa B (NF-kappa B) translocation and TNF -alpha secretion in CHO-CD14 cells and monocytes, respectively, while mAb enhancement of non-mCD14-mediated LPS uptake stimulated these acti vities, LPS-specific Abs thus mediate anti-inflammatory and proinflamm atory functions, respectively, by preventing target cell uptake of LPS through mCD14 and augmenting uptake through CR1 or other cell recepto rs.