Chylomicron-bound endotoxin selectively inhibits NF-kappaB activation in rat hepatocytes.
Triglyceride-rich lipoproteins (chylomicrons and very low-density lipoproteins) bind endotoxin (lipopolysaccharide [LPS]), forming lipoprotein-LPS complexes, and protect against endotoxic shock and death in rodent models of gram-negative sepsis. Hepatocytes play a central role in the protective process, as demonstrated by the increased uptake of chylomicron (CM)-bound LPS by these cells. We have previously reported that CM-LPS complexes inhibit nitric oxide (NO) production by hepatocytes as compared with LPS or CM alone. Herein, we report that CM-LPS selectively inhibits NF-kappaB in hepatocytes. Pretreating cultured primary hepatocyte spheroids with CM-bound LPS inhibited cytokine-induced NF-kappaB activation by approximately 60% vs. untreated control cells (P < 0.03). The lipoprotein-mediated inhibition of NF-kappaB was non-toxic, selective, and associated with inhibition of IkappaB degredation. These data indicate that the mechanism by which CM protect against LPS involves inhibition of the hepatocellular response to proinflammatory stimulation and also support a role for triglyceride-rich lipoproteins as components of the innate host immune response to infection.
Kumwenda
Zindaba L
ZL
University of California Surgical Research Laboratory at San Francisco General Hospital, University of California, 94110-3518, USA.
Wong
Cindy B
CB
Johnson
Jennifer A
JA
Gosnell
Jessica E
JE
Welch
William J
WJ
Harris
Hobart W
HW
D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D002914:Chylomicrons / Q000494:pharmacology; D004195:Disease Models, Animal; D004731:Endotoxins / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D015151:Immunoblotting; D008297:Male; D016328:NF-kappa B / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D011336:Probability; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D012680:Sensitivity and Specificity; D012772:Shock, Septic / Q000503:physiopathology
D002914:Chylomicrons; D004731:Endotoxins; D016328:NF-kappa B; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase