Interleukin-1 beta Is Crucial for the Induction of Coronary Artery Inflammation in a Mouse Model of Kawasaki Disease

Article

关键词: CYTOPLASMIC INCLUSION-BODIES;    GAMMA-GLOBULIN TREATMENT;    INTRAVENOUS IMMUNOGLOBULIN;    TREATMENT FAILURE;    ANIMAL-MODEL;    CHILDREN;    PATHOGENESIS;    RETREATMENT;    ANEURYSM;    LESSONS;   

DOI  :  10.1161/CIRCULATIONAHA.111.072769

来源: SCIE

【 摘 要 】

Background-Kawasaki disease (KD) is the most common cause of acute vasculitis and acquired cardiac disease in US children. Untreated, children may develop coronary artery aneurysms, myocardial infarction, and sudden death as a result of the illness. Up to a third of KD patients fail to respond to intravenous immunoglobulin, the standard therapy, and alternative treatments are being investigated. Genetic studies have indicated a possible role for interleukin (IL)-1 beta in KD. We therefore explored the role of IL-1 beta in a murine model of KD. Methods and Results-Using an established mouse model of KD that involves injection of Lactobacillus casei cell wall extract (LCWE), we investigated the role of IL-1 beta and caspase-1 (activated by the inflammasome and required for IL-1 beta maturation) in coronary arteritis and evaluated the efficacy of IL-1 receptor antagonist as a potential treatment. LCWE-induced IL-1 beta maturation and secretion were dependent on the NLRP3 inflammasome in macrophages. Both caspase-1-deficient and IL-1 receptor-deficient mice were protected from LCWE-induced coronary lesions. Injection of recombinant IL-1 beta into caspase-1-deficient mice restored the ability of LCWE to cause coronary lesions in response to LCWE. Furthermore, daily injections of the IL-1 receptor antagonist prevented LCWE-mediated coronary lesions up to 3 days after LCWE injection. Conclusions-Our results strongly suggest that caspase-1 and IL-1 beta play critical roles in the development of coronary lesions in this KD mouse model, blocked by IL-1 receptor antagonist. Therefore, anti-IL-1 beta treatment strategies may constitute an effective, more targeted treatment of KD to prevent coronary lesions. (Circulation. 2012;125:1542-1550.)

【 授权许可】

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