Lipopolysaccharide: neutralization by polymyxin B shuts down the signaling pathway of nuclear factor kappaB in peripheral blood mononuclear cells, even during activation.
BACKGROUND
There have been many studies on anti-lipopolysaccharide (LPS) agents and LPS-neutralizing agents; however, there have been no reports on the changes in clinical status and mediators that occur when these agents are used. Polymyxin (PMX) (treatment using a column containing polymyxin B-immobilized fiber) removed circulating endotoxin, and reduced various cytokines within 120 min, even in patients with high levels of plasma cytokines. Our purpose was examine the mechanisms of PMX treatment by which plasma cytokines are reduced by endotoxin neutralization with polymyxin B, even during therapy for sepsis and/or endotoxin shock.


METHODS
We studied the interaction between nuclear factor kappaB (NF-kappaB) binding activity and tumor necrosis factor alpha (TNF-alpha) secretion in an experimental system using LPS-stimulated human peripheral blood mononuclear cells (PBMCs), after neutralization of LPS with polymyxin B. PBMCs were incubated with LPS in vitro, and TNF-alpha secretion and NF-kappaB activation were assessed. We then studied the changes in NF-kappaB activation and TNF-alpha secretion when both polymyxin B and LPS were added simultaneously and when polymyxin B was added after 30 or 120 min of incubation with LPS.


RESULTS
Immediate inhibition of NF-kappaB binding activity and suppression of TNF-alpha secretion were observed after LPS neutralization with polymyxin B regardless of whether PBMCs were already producing TNF-alpha.


CONCLUSIONS
These findings may indicate one of the mechanisms operating in the clinical changes that occur after circulating endotoxin removal, and are likely to have therapeutic value, even for patients with high proinflammatory cytokine levels.
Tsuzuki
H
H
First Department of Surgery, Shiga University of Medical Science, Seta-tsukinowa-cho, Otsu-city, Shiga, 520-2192, Japan. tsuzukih@smile.ocn.ne.jp
Tani
T
T
Ueyama
H
H
Kodama
M
M
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D006801:Humans; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D011112:Polymyxin B / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000900:Anti-Bacterial Agents; D008070:Lipopolysaccharides; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D011112:Polymyxin B