Effect of simvastatin or its combination with ezetimibe on Toll-like receptor expression and lipopolysaccharide - induced cytokine production in monocytes of hypercholesterolemic patients.
OBJECTIVE
Toll-like receptors (TLRs) are key players in the innate immune system. Recently, a pivotal role of TLR2 and TLR4 has been recognized in atherogenesis. We investigated the effect of simvastatin monotherapy or its combination with ezetimibe on TLR2 and TLR4 membrane expression and on lipopolysaccharide (LPS)-induced interleukin-1β (IL-1β) and interleukin-6 (IL-6) production in peripheral blood monocytes of patients with primary hypercholesterolemia.


METHODS
This was a prospective, randomized, open-label, blinded endpoint study. After a 3-month period of lifestyle changes patients (n = 60) (mean age 55 ± 13) with LDL-cholesterol levels above those recommended by the NCEP ATP III, were randomly allocated to open-label simvastatin 40 mg (n = 30) or simvastatin/ezetimibe 10/10 mg (n = 30) daily. Both groups were similar with regard to demographics, risk factors, medications and baseline lipid values. TLR2 and TLR4 membrane expression in monocytes, LPS-induced intracellular production of IL-1β and IL-6 were assessed by flow cytometry at baseline and 3 months post-treatment in both patient groups, as well as in 30 age- and sex-matched normolipidemic controls.


RESULTS
Hypercholesterolemic patients exhibited higher TLR2 and TLR4 membrane expression compared with controls (p < 0.02). LPS induced a significant increase in the intracellular levels of IL-1β and IL-6 in all groups however both patient groups exhibited significantly lower levels compared with controls. Three months of treatment with either simvastatin or its combination with ezetimibe resulted in a significant reduction of TLR2 and TLR4 expression (p < 0.01 compared with baseline values) with no intergroup differences. Furthermore, in both groups the post-treatment values of LPS-induced IL-1β and IL-6 production were significantly lower compared with baseline (p < 0.05 for all comparisons).


CONCLUSIONS
A high simvastatin dose or the combination of a low-dose simvastatin with ezetimibe reduce to a similar extent TLR2, TLR4 membrane expression and LPS-induced IL-6 and IL-1β production in monocytes of hypercholesterolemic patients. The pathophysiological significance of these effects regarding atherosclerosis, reserves further investigation.
Department of Internal Medicine, School of Medicine, University of Ioannina, 45110 Ioannina, Greece.
Elisavet
E
Moutzouri
Constantinos C
CC
Tellis
Kleopatra
K
Rousouli
Evangelos N
EN
Liberopoulos
Haralambos J
HJ
Milionis
Moses S
MS
Elisaf
Alexandros D
AD
Tselepis
D000328:Adult; D000368:Aged; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D001384:Azetidines / Q000627:therapeutic use*; D016207:Cytokines / Q000097:blood*; D015536:Down-Regulation; D004338:Drug Combinations; D000069499:Ezetimibe, Simvastatin Drug Combination; D005260:Female; D005434:Flow Cytometry; D006115:Greece; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D053583:Interleukin-1beta / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology; D011446:Prospective Studies; D019821:Simvastatin / Q000627:therapeutic use*; D013997:Time Factors; D051195:Toll-Like Receptor 2 / Q000097:blood / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000097:blood / Q000187:drug effects; D051193:Toll-Like Receptors / Q000097:blood / Q000187:drug effects*; D016896:Treatment Outcome
D000924:Anticholesteremic Agents; D001384:Azetidines; D016207:Cytokines; D004338:Drug Combinations; D000069499:Ezetimibe, Simvastatin Drug Combination; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C508600:IL6 protein, human; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D019821:Simvastatin