LPS-induced cytokine production and expression of LPS-receptors by peripheral blood mononuclear cells of patients with familial hypercholesterolemia and the effect of HMG-CoA reductase inhibitors.
Inflammatory processes play an important role in atherogenesis, and proinflammatory cytokines such as interleukin-1beta (IL-1beta), IL-6, and tumour necrosis factor alpha (TNFalpha) are thought to be mediators in this phenomenon. We have previously established that peritoneal macrophages of LDL-receptor knock-out mice, which are hypercholesterolemic and are prone to atherosclerosis, have an increased LPS-induced cytokine production capacity, ex vivo. The aim of the present study was to investigate whether the process leading to atherosclerosis in patients with familial hypercholesterolemia (FH) is associated with increased cytokine production capacity of peripheral blood mononuclear cells (PBMC) and/or increased expression of adhesion molecules on monocytes and lymphocytes. Furthermore, we assessed the effect of cholesterol lowering on the production capacity of PBMC, as these drugs are beneficial with regard to cardiovascular diseases. LPS-induced IL-1beta and TNFalpha production by PBMCs of 21 heterozygous FH patients appeared to be similar to the production by PBMCs of 21 healthy volunteers. In addition, expression of the LPS-receptors CD14 and beta2-integrins in nine patients and controls did not differ either. In a second series of experiments, HMG-CoA synthesis inhibitors were ineffective to change the LPS-induced production by PBMC of IL-1alpha, IL-1beta, IL-1 receptor antagonist (IL-1ra), IL-6, and TNFalpha. In conclusion, cytokine production capacity of blood cells or the expression of LPS-receptors on circulating PBMC do not deviate in subjects with FH and also do not change as a result of treatment with cholesterol synthesis inhibitors.
Department of Medicine, University Hospital Nijmegen, The Netherlands.
N
N
de Bont
M G
MG
Netea
C
C
Rovers
T
T
Smilde
P N
PN
Demacker
J W
JW
van der Meer
A F
AF
Stalenhoef
D000818:Animals; D000924:Anticholesteremic Agents / Q000627:therapeutic use; D000069059:Atorvastatin; D018845:CD11 Antigens / Q000378:metabolism; D015331:Cohort Studies; D016207:Cytokines / Q000097:blood*; D004311:Double-Blind Method; D006538:Heptanoic Acids / Q000627:therapeutic use; D006579:Heterozygote; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006938:Hyperlipoproteinemia Type II / Q000097:blood* / Q000188:drug therapy; D008055:Lipids / Q000097:blood; D018950:Lipopolysaccharide Receptors / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D011758:Pyrroles / Q000627:therapeutic use; D019821:Simvastatin / Q000627:therapeutic use
D000924:Anticholesteremic Agents; D018845:CD11 Antigens; D016207:Cytokines; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D011758:Pyrroles; D000069059:Atorvastatin; D019821:Simvastatin