title: Monocyte release of tumor necrosis factor-alpha and interleukin-1beta in primary type IIa and IIb dyslipidemic patients treated with statins or fibrates.
abstract: Both 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) as well as peroxisome proliferator-activated receptor (PPAR)alpha 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-alpha (TNFalpha) and interleukin-1beta 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 TNFalpha (types IIa and IIb dyslipidemias) and interleukin-1beta (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 TNFalpha and interleukin-1beta, 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 TNFalpha and interleukin-1beta production by activated monocytes. Both HMG-CoA reductase inhibitors and PPARalpha 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.
authors.affiliation: Department of Clinical Pharmacology, Medical University of Silesia, Medyków 18, PL 40-752 Katowice, Poland.
authors.forename: Bogusław
authors.initials: B
authors.lastname: Okopień
authors.forename: Robert
authors.initials: R
authors.lastname: Krysiak
authors.forename: Jan
authors.initials: J
authors.lastname: Kowalski
authors.forename: Andrzej
authors.initials: A
authors.lastname: Madej
authors.forename: Dariusz
authors.initials: D
authors.lastname: Belowski
authors.forename: Marek
authors.initials: M
authors.lastname: Zieliński
authors.forename: Zbigniew S
authors.initials: ZS
authors.lastname: Herman
mesh_terms: D000328:Adult; D000924:Anticholesteremic Agents / Q000494:pharmacology; D002097:C-Reactive Protein / Q000378:metabolism; D002995:Clofibric Acid / Q000031:analogs & derivatives / Q000494:pharmacology*; D016207:Cytokines / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood; D050171:Dyslipidemias / Q000097:blood / Q000209:etiology / Q000378:metabolism*; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D005260:Female; D058607:Fibric Acids; D000077340:Fluvastatin; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006937:Hypercholesterolemia / Q000097:blood / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D007249:Inflammation / Q000473:pathology; D007375:Interleukin-1 / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D047493:PPAR alpha / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D000924:Anticholesteremic Agents; D016207:Cytokines; D005229:Fatty Acids, Monounsaturated; D058607:Fibric Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents; D007211:Indoles; D007375:Interleukin-1; D047493:PPAR alpha; D014409:Tumor Necrosis Factor-alpha; D000077340:Fluvastatin; D002995:Clofibric Acid; D002097:C-Reactive Protein; C019304:ciprofibrate