Journal
CIRCULATION-HEART FAILURE
Volume 5, Issue 3, Pages 366-375Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCHEARTFAILURE.111.963769
Keywords
myocarditis; cytokines; inflammation; idiopathic dilated cardiomyopathy; eosinophils
Categories
Funding
- National Institutes of Health (NIH) [R01 HL087033]
- National Center for Research Resources, NIH [UL1 RR 025005]
- NIH Roadmap for Medical Research
- American Heart Association
- NIH [R01 HL087033, R56HL077611]
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Background-IL-33 through its receptor ST2 protects the heart from myocardial infarct and hypertrophy in animal models but, paradoxically, increases autoimmune disease. In this study, we examined the effect of IL-33 or ST2 administration on autoimmune heart disease. Methods and Results-We used pressure-volume relationships and isoproterenol challenge to assess the effect of recombinant (r) IL-33 or rST2 (eg, soluble ST2) administration on the development of autoimmune coxsackievirus B3 myocarditis and dilated cardiomyopathy in male BALB/c mice. The rIL-33 treatment significantly increased acute perimyocarditis (P=0.006) and eosinophilia (P=1.3 x 10(-5)), impaired cardiac function (maximum ventricular power, P = 0.0002), and increased ventricular dilation (end-diastolic volume, P=0.01). The rST2 treatment prevented eosinophilia and improved heart function compared with rIL-33 treatment (ejection fraction, P=0.009). Neither treatment altered viral replication. The rIL-33 treatment increased IL-4, IL-33, IL-1 beta, and IL-6 levels in the heart during acute myocarditis. To determine whether IL-33 altered cardiac function on its own, we administered rIL-33 to undiseased mice and found that rIL-33 induced eosinophilic pericarditis and adversely affected heart function. We used cytokine knockout mice to determine that this effect was due to IL-33-mediated signaling but not to IL-1 beta or IL-6. Conclusions-We show for the first time to our knowledge that IL-33 induces eosinophilic pericarditis, whereas soluble ST2 prevents eosinophilia and improves systolic function, and that IL-33 independently adversely affects heart function through the IL-33 receptor. (Circ Heart Fail. 2012;5:366-375.)
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