title: The role of atorvastatin in regulating the immune response leading to vascular damage in a model of Kawasaki disease.
abstract: 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.
authors.affiliation: Cell Biology Program, The Hospital for Sick Children Research Institute, Toronto, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Blankier
authors.forename: B W
authors.initials: BW
authors.lastname: McCrindle
authors.forename: S
authors.initials: S
authors.lastname: Ito
authors.forename: R S M
authors.initials: RS
authors.lastname: Yeung
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000633:toxicity; D001167:Arteritis / Q000150:complications / Q000188:drug therapy*; D000069059:Atorvastatin; D002473:Cell Wall / Q000276:immunology; D003323:Coronary Aneurysm / Q000209:etiology / Q000517:prevention & control*; D003327:Coronary Disease / Q000150:complications / Q000188:drug therapy*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D006538:Heptanoic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D007155:Immunologic Factors / Q000494:pharmacology / Q000627:therapeutic use*; D007780:Lacticaseibacillus casei / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics; D008798:Mevalonic Acid / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009080:Mucocutaneous Lymph Node Syndrome / Q000276:immunology*; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D013047:Specific Pathogen-Free Organisms; D018089:Superantigens / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000942:Antigens, Bacterial; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007155:Immunologic Factors; D011758:Pyrroles; D018089:Superantigens; D014409:Tumor Necrosis Factor-alpha; D000069059:Atorvastatin; D020780:Matrix Metalloproteinase 9; D008798:Mevalonic Acid