Hyperlipoproteinemia affects cytokine production in whole blood samples ex vivo. The influence of lipid-lowering therapy.
Low-density lipoprotein (LDL)-receptor deficient mice, thus hypercholesterolemic, combine protection against infection with an ex vivo two- to threefold higher pro-inflammatory cytokine production in macrophages. A pro-inflammatory cytokine profile ex-vivo is also associated with survival of gram-negative sepsis in man. We hypothesized that high lipoprotein levels would be associated with a pro-inflammatory cytokine production and could explain the resistance to fatal infection. We treated 10 patients with familial hypercholesterolemia (FH) with HMG-CoA reductase inhibitors, and 13 patients with endogenous hypertriglyceridemia (HTG) with fibrates. Blood samples were stimulated ex vivo with lipopolysaccharide (LPS), to assess the cytokine production capacity. FH patients had significantly lower tumor necrosis factor-alpha (TNF-alpha) production, compared to normolipidemic controls (P=0. 001). Lipid lowering treatment in FH patients did not affect TNF-alpha production. HTG patients showed significantly higher TNF-alpha production at baseline than matched normolipidemic controls (P<0.001), while lowering of serum triglycerides in these patients resulted in a significant decrease in TNF-alpha production (P=0.019). The IL-10 production was not affected. These data refute our hypothesis that high LDL-cholesterol levels are associated with a pro-inflammatory cytokine production capacity. In contrast, the study suggests that very-low-density lipoprotein (VLDL) in hypertriglyceridemic patients augments TNF-alpha production.
Mohrschladt
M F
MF
Department of General Internal Medicine, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands. mfmohrschladt@aig.azl.nl
Weverling-Rijnsburger
A W
AW
de Man
F H
FH
Stoeken
D J
DJ
Sturk
A
A
Smelt
A H
AH
Westendorp
R G
RG
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D000069059:Atorvastatin; D001629:Bezafibrate / Q000627:therapeutic use*; D018592:Cross-Over Studies; D016207:Cytokines / Q000096:biosynthesis / Q000097:blood*; D004311:Double-Blind Method; D005260:Female; D006538:Heptanoic Acids / Q000627:therapeutic use*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000188:drug therapy; D006951:Hyperlipoproteinemias / Q000097:blood* / Q000188:drug therapy*; D015228:Hypertriglyceridemia / Q000097:blood / Q000188:drug therapy; D000960:Hypolipidemic Agents / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011758:Pyrroles / Q000627:therapeutic use*; D012016:Reference Values
D000924:Anticholesteremic Agents; D016207:Cytokines; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents; D011758:Pyrroles; D000069059:Atorvastatin; D001629:Bezafibrate