Abstract
This study investigated the effect of simvastatin on the expression of OX40 and OX40 ligand (OX40L) in vitro and in vivo. OX40 and OX40L mRNA and protein levels were measured in human peripheral blood mononuclear cells, using reverse transcription–polymerase chain reaction and Western blot, respectively, in response to simvastatin alone or given in combination with interferon-γ, mevalonate or GW9662, a peroxisome proliferator-activated receptor-γ (PPAR-γ) antagonist. Simvastatin induced down-regulation of OX40 and OX40L mRNA and protein in a concentration-dependent manner, and antagonized the interferon-γ-induced increase in OX40 and OX40L mRNA and protein levels. Mevalonate, but not GW9662, reversed the simvastatin-induced down-regulation of OX40 and OX40L expression, indicating that these effects were mediated through the mevalonate pathway. Serum levels of soluble OX40L and matrix metalloproteinase 9 levels were significantly reduced in patients with atherosclerotic cerebral infarction who were treated for 6 months with routine therapy plus simvastatin (n = 46) compared with patients receiving routine therapy alone (n = 30). These findings improve our understanding of the anti-inflammatory and immunomodulatory properties of simvastatin treatment for atherosclerotic disorders.