Increased expression of interleukin-1 in coronary artery disease with downregulatory effects of HMG-CoA reductase inhibitors.
BACKGROUND
Inflammation is important in atherogenesis. Interleukin (IL)-1 is the prototypic inflammatory cytokine. We hypothesized a dysbalance between inflammatory and anti-inflammatory mediators in the IL-1 family in coronary artery disease (CAD) and a possible modulation of these mediators by HMG-CoA inhibitors (statins).


RESULTS
In a microarray screening experiment examining peripheral blood mononuclear cells (PBMCs) from 6 CAD patients and 4 healthy control subjects, IL-1beta was identified as 1 of 25 genes whose expression were upregulated in CAD and downregulated by statins. In the following, we studied the role of IL-1beta and related mediators in CAD. Our major findings were as follows. (1) Although mRNA levels of IL-1alpha and IL-1beta were markedly reduced in PBMCs from CAD patients after 6 months of simvastatin (20 mg/d, n=15) and atorvastatin (80 mg/d, n=15) therapy, the reduction in IL-1 receptor antagonist (IL-1Ra) was more modest. Statins also reduced the spontaneous release of IL-1beta and IL-1Ra from PBMCs in CAD patients. (2) mRNA levels of IL-1alpha, IL-1beta, and IL-1Ra were increased in PBMCs from patients with stable (n=20) and unstable (n=20) angina compared with healthy control subjects (n=15). Although the unstable patients had particularly high levels of IL-1beta and IL-1alpha, IL-1Ra was not correspondingly increased. (3) IL-1beta induced release of proatherogenic cytokines from PBMCs, whereas atorvastatin partly abolished this effect.


CONCLUSIONS
Our findings suggest that cytokines in the IL-1 family may represent therapeutic targets in CAD. The ability of statins to modulate these cytokines in an anti-inflammatory direction underscores their immunomodulatory potential.
Waehre
Torgun
T
Research Institute of Internal Medicine, Rikshospitalet, N-0027 Oslo, Norway. torgun.wahre@klinmed.uio.no
Yndestad
Arne
A
Smith
Camilla
C
Haug
Terje
T
Tunheim
Siv Haugen
SH
Gullestad
Lars
L
Frøland
Stig S
SS
Semb
Anne G
AG
Aukrust
Pål
P
Damås
Jan K
JK
D000787:Angina Pectoris / Q000235:genetics / Q000276:immunology; D000789:Angina, Unstable / Q000235:genetics / Q000276:immunology; D000069059:Atorvastatin; D003324:Coronary Artery Disease / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D003430:Cross-Sectional Studies; D015536:Down-Regulation; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006538:Heptanoic Acids / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D019821:Simvastatin / Q000494:pharmacology / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007375:Interleukin-1; D011758:Pyrroles; D014409:Tumor Necrosis Factor-alpha; D000069059:Atorvastatin; D019821:Simvastatin