Superantigens have been implicated in a number of diseases including
Kawasaki disease (KD), a multi-system
vasculitis resulting in coronary artery
aneurysms. We have characterized a murine disease model in which coronary
arteritis is induced by a novel
superantigen found in Lactobacillus casei cell wall extract (LCWE). Using this animal model of KD, we have identified three pathogenic steps leading to coronary artery
aneurysm formation. These steps include T cell activation and proliferation, production of the proinflammatory
cytokine tumour
necrosis factor (TNF)-α and up-regulation of
matrix metalloproteinase 9 (MMP-9), an elastolytic
protease. In addition to their
cholesterol-lowering effects, 3-hydroxy-3-methylglutaryl (HMG)
coenzyme A (
CoA)
reductase inhibitors (
statins) have pleotropic immunomodulatory properties. Thus, we examined the effect of
atorvastatin in modulating each of these three critical pathogenic processes leading to
aneurysm formation in the disease model.
Atorvastatin inhibited lymphocyte proliferation in response to
superantigen stimulation in a dose-dependent manner. This inhibition was also observed for production of soluble
mediators of inflammation including
interleukin (IL)-2 and TNF-α. The inhibitory effect on proliferation was rescued completely by
mevalonic acid, confirming that the mechanism responsible for this inhibitory activity on immune activation was inhibition of
HMG-CoA reductase. Similarly, TNF-α-induced MMP-9 production was reduced in a dose-dependent manner in response to
atorvastatin. Inhibition of extracellular-regulated
kinase (ERK) phosphorylation appears to be the mechanism responsible for inhibition of MMP-9 production. In conclusion,
atorvastatin is able to inhibit critical steps known to be important in the development of
coronary aneurysms, suggesting that
statins may have therapeutic benefit in patients with KD.