Apolipoprotein E knock-out mice are highly susceptible to endotoxemia and Klebsiella pneumoniae infection.
Lipoproteins are able to neutralize bacterial lipopolysaccharide (LPS) and thereby inhibit the proinflammatory cytokine response. In a previous study, we demonstrated that hypercholesterolemic low density lipoprotein receptor knock-out (LDLr-/-) mice are protected against lethal endotoxemia and gram-negative infection. In the present study we investigated the susceptibility of apolipoprotein E knock-out mice (apoE-/-) to LPS and to Klebsiella pneumoniae. These mice have increased plasma lipoprotein concentrations in the very low density lipoprotein (VLDL)-sized fraction. Despite 8 -fold higher plasma cholesterol levels compared to controls, and in contrast to LDLr-/- mice, apoE-/- mice were significantly more susceptible to endotoxemia and to K. pneumoniae infection. Circulating TNFalpha concentrations after intravenously injected LPS were 4 - to 5-fold higher in apoE-/- mice, whereas IL-1alpha, IL-1beta, and IL-6 did not differ. This TNF response was not due to an increased cytokine production capacity of cells from apoE-/- mice, as ex vivo cytokine production in response to LPS did not differ between apoE-/- and control mice. The LPS-neutralizing capacity of apoE-/- plasma was significantly less than that of controls. Most likely, the absence of apoE itself in the knock-out mice explains the failure to neutralize LPS, despite the very high cholesterol concentrations.
de Bont
N
N
Division of General Internal Medicine, Department of Medicine, University Hospital Nijmegen, 6500 HB Nijmegen, The Netherlands.
Netea
M G
MG
Demacker
P N
PN
Verschueren
I
I
Kullberg
B J
BJ
van Dijk
K W
KW
van der Meer
J W
JW
Stalenhoef
A F
AF
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D002784:Cholesterol / Q000097:blood; D016207:Cytokines / Q000097:blood; D004198:Disease Susceptibility; D019446:Endotoxemia / Q000097:blood / Q000401:mortality; D007710:Klebsiella Infections / Q000097:blood / Q000401:mortality; D007711:Klebsiella pneumoniae; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000493:pharmacokinetics; D008074:Lipoproteins / Q000097:blood; D053419:Lipoproteins, IDL; D008077:Lipoproteins, LDL / Q000097:blood; D008079:Lipoproteins, VLDL / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D001057:Apolipoproteins E; D016207:Cytokines; D008070:Lipopolysaccharides; D008074:Lipoproteins; D053419:Lipoproteins, IDL; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D014409:Tumor Necrosis Factor-alpha; D002784:Cholesterol