Monophosphoryl lipid A inhibits neutrophil priming by lipopolysaccharide.
It is known that lipopolysaccharides (endotoxin) prime neutrophils for oxygen radical production. Monophosphoryl lipid A is a nontoxic derivative of lipid A that protects against lethal endotoxemia. We examined the effects of Salmonella minnesota monophosphoryl lipid A on S. minnesota lipopolysaccharide-induced priming of neutrophil superoxide anion generation. Human neutrophils were preincubated with and without either lipopolysaccharide or monophosphoryl lipid A before stimulation with 10(-5) formyl-norleucyl-leucyl-phenylalanine. Neutrophil priming reached a plateau at a concentration of 100 ng/ml of lipopolysaccharide, where superoxide anion generation increased from 10.1 +/- 0.8 to 25.2 +/- 1.7 nmol superoxide anions/10(6) neutrophils/10 min (p less than 0.01). In contrast, monophosphoryl lipid A did not exhibit any priming activity. Monophosphoryl lipid A also exhibited a time-dependent inhibitory effect on lipopolysaccharide-induced priming of neutrophils, which was maximal when monophosphoryl lipid A was added 15 minutes before lipopolysaccharide. Preincubation with monophosphoryl lipid A induced a dose-dependent inhibition of neutrophil priming by 1000 ng/ml lipopolysaccharide. Neutrophil superoxide anion generation decreased by 47% from 19.0 +/- 0.6 to 10.0 +/- 0.7 nmol superoxide anions/10(6) neutrophils/10 min by 2000 ng/ml monophosphoryl lipid A (p less than 0.01). These data indicate that monophosphoryl lipid A does not enhance neutrophil superoxide generation in response to formyl-norleucyl-leucyl-phenylalanine. Monophosphoryl lipid A also inhibits lipopolysaccharide-induced priming in a dose-dependent manner that may reflect blocking of lipopolysaccharide by monophosphoryl lipid A at cellular binding sites.
Heiman
D F
DF
Department of Medicine, University of Health Sciences, Chicago Medical School, Illinois.
Astiz
M E
ME
Rackow
E C
EC
Rhein
D
D
Kim
Y B
YB
Weil
M H
MH
D004305:Dose-Response Relationship, Drug; D006801:Humans; D008050:Lipid A / Q000031:analogs & derivatives* / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
D008050:Lipid A; D008070:Lipopolysaccharides; D013481:Superoxides; C048436:monophosphoryl lipid A; D010100:Oxygen