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 hypothesis that anti-LPS Abs neutralize endotoxin by blocking cellular uptake through mCD14. Ab-associated changes in the uptake and cellular distribution of FITC-LPS were assessed by flow cytometry and laser scanning confocal microscopy in human CD14-transfected Chinese hamster ovary 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-specific mAb concurrently enhanced complement-dependent LPS uptake by monocytes through complement receptor-1 (CR1) and uptake by CHO-CD14 cells involving another heat-labile serum factor(s) and cell-associated recognition molecule(s). Core-specific mAb inhibited mCD14-mediated uptake of homologous and heterologous LPS, while producing less concurrent enhancement of non-mCD14-mediated LPS uptake. The modulation by anti-LPS mAbs of mCD14-mediated LPS uptake was associated with inhibition of LPS-induced nuclear factor-kappaB (NF-kappaB) translocation and TNF-alpha secretion in CHO-CD14 cells and monocytes, respectively, while mAb enhancement of non-mCD14-mediated LPS uptake stimulated these activities. LPS-specific Abs thus mediate anti-inflammatory and proinflammatory functions, respectively, by preventing target cell uptake of LPS through mCD14 and augmenting uptake through CR1 or other cell receptors.
Pollack
M
M
Department of Medicine, Uniformed Services University of the Health Sciences, F. Edward Hébert School of Medicine, Bethesda, Maryland 20814, USA. pollack@usuhsb.usuhs.mil
Ohl
C A
CA
Golenbock
D T
DT
Di Padova
F
F
Wahl
L M
LM
Koles
N L
NL
Guelde
G
G
Monks
B G
BG
D000328:Adult; D000818:Animals; D000907:Antibodies, Bacterial / Q000737:chemistry / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000494:pharmacology*; D000942:Antigens, Bacterial / Q000737:chemistry / Q000276:immunology; D001692:Biological Transport / Q000276:immunology; D016466:CHO Cells; D006224:Cricetinae; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000209:etiology / Q000276:immunology; D018950:Lipopolysaccharide Receptors / Q000276:immunology; D008070:Lipopolysaccharides / Q000097:blood / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D011487:Protein Conformation; D017463:Receptors, Complement 3b / Q000276:immunology
D000907:Antibodies, Bacterial; D000911:Antibodies, Monoclonal; D000942:Antigens, Bacterial; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D016328:NF-kappa B; D017463:Receptors, Complement 3b