Cihakova Daniela, Barin Jobert G, Afanasyeva Marina, Kimura Miho, Fairweather DeLisa, Berg Michael, Talor Monica V, Baldeviano G Christian, Frisancho Sylvia, Gabrielson Kathleen, Bedja Djahida, Rose Noel R
Johns Hopkins University, Department of Pathology, Division of Immunology, Ross 648, 720 Rutland Ave., Baltimore, MD 21205, USA.
Am J Pathol. 2008 May;172(5):1195-208. doi: 10.2353/ajpath.2008.070207. Epub 2008 Apr 10.
We report here that interleukin (IL)-13 protects BALB/c mice from myocarditis, whether induced by peptide immunization or by viral infection. In contrast to mild disease in IL-4 knockout (KO) BALB/c mice, IL-13 KO BALB/c mice developed severe coxsackievirus B3 (CVB3)-induced autoimmune myocarditis and myocarditogenic peptide-induced experimental autoimmune myocarditis. Such severe disease was characterized by increased cardiac inflammation, increased total intracardiac CD45(+) leukocytes, elevated anti-cardiac myosin autoantibodies, and increased cardiac fibrosis. Echocardiography revealed that IL-13 KO mice developed severe dilated cardiomyopathy with impaired cardiac function and heart failure. Hearts of IL-13 KO mice had increased levels of the proinflammatory and profibrotic cytokines IL-1beta, IL-18, interferon-gamma, transforming growth factor-beta1, and IL-4 as well as histamine. The hallmark of the disease in IL-13 KO mice was the up-regulation of T-cell responses. CD4(+) T cells were increased in IL-13 KO hearts both proportionally and in absolute number. Splenic T cells from IL-13 KO mice were highly activated, and myosin stimulation additionally increased T-cell proliferation. CD4(+)CD25(+)Foxp3(+) regulatory T-cell numbers were decreased in the spleens of IL-13 KO mice. IL-13 deficiency led to decreased levels of alternatively activated CD206(+) and CD204(+) macrophages and increased levels of classically activated macrophages. IL-13 KO mice had increased caspase-1 activation, leading to increased production of both IL-1beta and IL-18. Therefore, IL-13 protects against myocarditis by modulating monocyte/macrophage populations and by regulating their function.
我们在此报告，白细胞介素（IL）-13可保护BALB/c小鼠免受心肌炎侵害，无论是由肽免疫诱导还是由病毒感染诱导。与IL-4基因敲除（KO）的BALB/c小鼠的轻度疾病不同，IL-13基因敲除的BALB/c小鼠发生了严重的柯萨奇病毒B3（CVB3）诱导的自身免疫性心肌炎和致心肌炎肽诱导的实验性自身免疫性心肌炎。这种严重疾病的特征是心脏炎症增加、心脏内总CD45(+)白细胞增加、抗心肌肌球蛋白自身抗体升高以及心脏纤维化增加。超声心动图显示，IL-13基因敲除小鼠发生了严重的扩张型心肌病，心脏功能受损并出现心力衰竭。IL-13基因敲除小鼠的心脏中促炎和促纤维化细胞因子IL-1β、IL-18、干扰素-γ、转化生长因子-β1、IL-4以及组胺的水平升高。IL-13基因敲除小鼠疾病的标志是T细胞反应上调。IL-13基因敲除心脏中的CD4(+) T细胞在比例和绝对数量上均增加。IL-13基因敲除小鼠的脾脏T细胞高度活化，肌球蛋白刺激进一步增加了T细胞增殖。IL-13基因敲除小鼠脾脏中CD4(+)CD25(+)Foxp3(+)调节性T细胞数量减少。IL-13缺乏导致交替活化的CD206(+)和CD204(+)巨噬细胞水平降低，经典活化的巨噬细胞水平升高。IL-13基因敲除小鼠的caspase-1活化增加，导致IL-1β和IL-18的产生均增加。因此，IL-13通过调节单核细胞/巨噬细胞群体及其功能来预防心肌炎。
