Statins inhibit toll-like receptor 4-mediated lipopolysaccharide signaling and cytokine expression

Abstract

Toll-like receptor 4 (TLR4) is the main receptor for Lipopolysaccharide (LPS). Two relatively common variants of the TLR4 gene are present, resulting in changes from aspartic acid (D) to glycine (G) at residue 299 and from threonine (T) to isoleucine (I) at residue 399, respectively. It has been shown that statins have a greater effect on lowering risk of cardiovascular events in individuals carrying the 299G allele than in those not carrying this allele. We investigated possible mechanisms underlying this synergy of statin treatment and TLR4 genotype. In cells expressing the 299D-399T TLR4, LPS activated the transcription factor NFkappaB and increased the expression of interleukin-6 and tumor necrosis factor-alpha, and these effects were reduced by pretreatment of the cells with pravastatin or simvastatin. LPS-induced NFkappaB activation and interleukin-6 and tumor necrosis factor-alpha expression were substantially reduced in cell expressing the 299G-399T or 299D-399I variant, and undetectable in cells expressing the 299G-399I TLR4. The 3-hydroxy-3-methylglutaryl coenzyme A pathway inhibitors, Y27632 and GGTI-286, exhibited a similar effect to statins, suggesting that the inhibitory effect of statins was mediated by the 3-hydroxy-3-methylglutaryl coenzyme A pathway. The results of this study indicate that the TLR4 variations and statins have an additive inhibitory effect on TLR4-mediated inflammatory response, providing a potential explanation for the finding that the beneficial effect of statins on cardiovascular risk is dependent on TLR4 genotype.