Increased expression of interleukin-1 in coronary artery disease with downregulatory effects of HMG-CoA reductase inhibitors

Torgun Waehre, Arne Yndestad, Camilla Smith, Terje Haug, Siv Haugen Tunheim, Lars Gullestad, Stig S Frøland, Anne G Semb, Pål Aukrust, Jan K Damås
Circulation 2004 April 27, 109 (16): 1966-72

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).

METHODS AND 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.

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