Marek Zieliński

Monocyte release of tumor necrosis factor-alpha and interleukin-1beta in primary type IIa and IIb dyslipidemic patients treated with statins or fibrates.

Both 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) as well as peroxisome proliferator-activated receptor (PPAR)α activators (fibrates) proved to be effective in the primary and secondary prevention of cardiovascular diseases. The benefits of hypolipemic therapy in cardiovascular diseases cannot be explained only by the lipid-lowering potential of these agents. The aim of this study was to clarify the effect of hypolipemic agents on proinflammatory cytokine release from human monocytes in relationship with their action on plasma levels of sensitive systemic marker of low-grade vascular inflammation. Plasma lipid and high-sensitivity C-reactive protein (hsCRP) levels, and the release of tumor necrosis factor-α (TNFα) and interleukin-1β from monocytes were assessed at baseline and 30 and 90 days following randomization of IIa dyslipidemic patients into fluvastatin or simvastatin groups and randomization of type IIb dyslipidemic patients to the micronized form of either ciprofibrate or fenofibrate. Lipopolysaccharide-stimulated monocytes from dyslipidemic patients released significantly more TNFα (types IIa and IIb dyslipidemias) and interleukin-1β (type IIa dyslipidemia) in comparison with monocytes in 59 age-, sex-, and weight-matched control subjects. Their baseline hsCRP levels were also higher. Both statins and fibrates reduced the release of TNFα and interleukin-1β, and lowered plasma hsCRP levels. The effects of hypolipemic agents on cytokine release and plasma hsCRP were unrelated to their lipid-lowering action. Our results have demonstrated that type IIa and IIb dyslipidemic patients exhibit the abnormal pattern of TNFα and interleukin-1β production by activated monocytes. Both HMG-CoA reductase inhibitors and PPARα activators normalize monocytic secretion of these cytokines, and this action may partially contribute to the systemic antiinflammatory effect of hypolipemic agents. The statin- and fibrate-induced suppression of proinflammatory cytokine release from monocytes seems to play a role in their beneficial effect on the incidence of cardiovascular events.

Hypolipidemic drugs affect monocyte IL-1beta gene expression and release in patients with IIa and IIb dyslipidemia.

Because atherosclerosis has been proven to be an inflammatory disease, it became obvious that the proper treatment of dyslipidemic patients should not only correct lipid parameters but also inhibit the inflammatory state. One of the crucial proinflammatory and procoagulant cytokines participating in the pathogenesis of atherosclerosis is interleukin-1β (IL-1β). Therefore, the aim of the study was to asses the effect of statin and fibrate therapy (for dyslipidemia IIa and IIb, respectively) on IL-1β gene expression and monocyte release evaluated in each patient. Additionally, the effect of hypolipidemic therapy on fibrinolysis was evaluated. The study was carried out in 37 patients: 12 with biochemically confirmed type IIa dyslipidemia (treated with atorvastatin), 12 with type IIb dyslipidemia (treated with fenofibrate), and 13 age- and sex-matched normolipidemic persons (control). IL-1β concentrations in cultured monocytes and PAI-1 (Plasminogen Activator Inhibitor) plasma levels were measured using the ELISA method. To evaluate the expression of IL-1β gene in monocytes, a semiquantitive RT-PCR procedure was performed. The results were normalized with the expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a housekeeping gene. Although IL-1β monocyte release was markedly elevated in patients with atherogenic dyslipidemias, IL-1β gene expression was only slightly and nonsignificantly higher in the studied groups versus control. We have observed significant reduction of IL-1β mRNA expression after 30-day treatment with the examined drugs (atorvastatin, 2.10 ± 0.50 versus 1.05 ± 0.15; P < 0.001, fenofibrate; 2.27 ± 0.48 versus 1.23 ± 0.27; P < 0.01). There was no significant difference between statin and fibrate effect on IL-1β mRNA expression. Similarly, we have noticed significant reduction of IL-1β release by cultured monocytes after 30-day statin therapy (133.0 ± 5.7 pg/mL versus 77.0 ± 3.6 pg/mL; P < 0.01) and fibrate therapy (143.9 ± 6.5 pg/mL versus 86.2 ± 5.9 pg/mL; P < 0.01). Besides this antiinflammatory effect, we have observed a 30% reduction of PAI-1 plasma levels in both treated groups. In conclusion, effective 1-month hypolipidemic therapy with atorvastatin or fenofibrate diminished plasma levels of proinflammatory and procoagulatory state markers.