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Simvastatin inhibits TLR8 signaling in primary human monocytes and spontaneous TNF production from rheumatoid synovial membrane cultures

journal contribution
posted on 2023-06-08, 23:32 authored by Lisa MullenLisa Mullen, Jason Ferdjani, Sandra SacreSandra Sacre
Simvastatin has been shown to have anti-inflammatory effects that are independent of its serum cholesterol lowering action, but the mechanisms by which these anti-inflammatory effects are mediated have not been elucidated. To explore the mechanism involved, the effect of simvastatin on Toll-like receptor (TLR) signalling in primary human monocytes was investigated. A short pre-treatment with simvastatin dose-dependently inhibited the production of tumor necrosis factor-a (TNF) in response to TLR8 (but not TLRs 2, 4, or 5) activation. Statins are known inhibitors of the cholesterol biosynthetic pathway, but intriguingly TLR8 inhibition could not be reversed by addition of mevalonate or geranylgeranyl pyrophosphate; downstream products of cholesterol biosynthesis. TLR8 signalling was examined in HEK 293 cells stably expressing TLR8, where simvastatin inhibited IKKa/ß phosphorylation and subsequent NF-?B activation without affecting the pathway to AP-1. Since simvastatin has been reported to have anti-inflammatory effects in RA patients and TLR8 signalling contributes to TNF production in human RA synovial tissue in culture, simvastatin was tested in these cultures. Simvastatin significantly inhibited the spontaneous release of TNF in this model which was not reversed by mevalonate. Together, these results demonstrate a hitherto unrecognized mechanism of simvastatin inhibition of TLR8 signalling that may in part explain its beneficial anti-inflammatory effects.

History

Publication status

  • Published

File Version

  • Accepted version

Journal

Molecular Medicine

ISSN

1528-3658

Publisher

Feinstein Institute for Medical Research

Issue

1

Volume

21

Page range

726-734

Department affiliated with

  • Clinical and Experimental Medicine Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2015-11-24

First Open Access (FOA) Date

2015-11-24

First Compliant Deposit (FCD) Date

2015-11-24

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