Resident cardiac mast cells degranulate and release preformed TNF-α, initiating the cytokine cascade in experimental canine myocardial ischemia/reperfusion
Resident cardiac mast cells degranulate and release preformed TNF-α, initiating the cytokine cascade in experimental canine myocardial ischemia/reperfusion
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DOI：
10.1161/01.cir.98.7.699
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发表时间：
1998-08-18
期刊：
影响因子：
37.8
通讯作者：
Entman, ML
中科院分区：
文献类型：
--
作者：
Frangogiannis, NG;Lindsey, ML;Entman, ML
背景：中性粒细胞诱导的心肌细胞损伤需要表达细胞间黏附分子(ICAM)-1和ICAM-1-CD11b/CD18黏附。我们以前已经证明了IL-6在缺血后心脏淋巴中的活性；IL-6是诱导心肌细胞ICAM-1的主要刺激因素。此外，我们还发现，IL-6mRNA的诱导在梗死心肌再灌流后很早就发生了，我们假设在再灌流时释放一种预先形成的上游细胞因子诱导IL-6在再灌流时渗透到白细胞中，方法和结果-在正常犬心肌中发现了TNF-α的结构性表达，而不是IL-1β的表达，并且主要定位于心脏肥大细胞。心肌缺血后心肌淋巴中组胺和肿瘤坏死因子-α迅速释放，证明心肌缺血后肥大细胞脱颗粒。FITC标记的亲和素组织化学研究表明，肥大细胞脱颗粒仅见于缺血心肌标本，免疫组织化学显示，脱颗粒肥大细胞是缺血心肌中肿瘤坏死因子-α的主要来源。再灌流心肌原位杂交显示IL-6mRNA定位于心肌缺血后15分钟内浸润性单个核细胞和缺血后心肌淋巴中的单个核细胞。此外，分离的犬单个核细胞与缺血后心脏淋巴孵育后可显著诱导IL-6mRNA的表达，其表达可被抗肿瘤坏死因子-α的中和抗体部分阻断。结论心肌缺血后心肌肥大细胞脱颗粒，释放组胺和肿瘤坏死因子-α等预形成的介质。我们认为，肥大细胞来源的肿瘤坏死因子-α可能是IL-6在白细胞中的表达上调和启动细胞因子级联反应的关键因素，这些细胞因子级联反应可导致心肌细胞ICAM-1的诱导和随后的中性粒细胞损伤。
Background-Neutrophil-induced cardiomyocyte injury requires the expression of myocyte intercellular adhesion molecule (ICAM)-1 and ICAM-1-CD11b/CD18 adhesion. We have previously demonstrated interleukin (IL)-6 activity in postischemic cardiac lymph; IL-6 is the primary stimulus for myocyte ICAM-1 induction. Furthermore, we found that induction of IL-6 mRNA occurred very early on reperfusion of the infarcted myocardium, We hypothesized that the release of a preformed upstream cytokine induced IL-6 in leukocytes infiltrating on reperfusion,Methods and Results-Constitutive expression of TNF-alpha and not IL-1 beta was demonstrated in the normal canine myocardium and was localized predominantly in cardiac mast cells. Mast cell degranulation in the ischemic myocardium was documented by demonstration of a rapid release of histamine and TNF-alpha in the cardiac lymph after myocardial ischemia, Histochemical studies with FITC-labeled avidin demonstrated degranulating mast cells only in ischemic samples of canine myocardium, Immunohistochemistry suggested that degranulating mast cells were the primary source of TNF-alpha in the ischemic myocardium. In situ hybridization studies of reperfused myocardium localized IL-6 mRNA in infiltrating mononuclear cells and in mononuclear cells appearing in the postischemic cardiac lymph within the first 15 minutes of reperfusion, Furthermore, isolated canine mononuclear cells incubated with postischemic cardiac lymph demonstrated significant induction of IL-6 mRNA, which was partially blocked with a neutralizing antibody to TNF-alpha.Conclusions-Cardiac mast cells degranulate after myocardial ischemia, releasing preformed mediators, such as histamine and TNF-alpha. We suggest that mast cell-derived TNF-alpha may be a crucial factor in upregulating IL-6 in infiltrating leukocytes and initiating the cytokine cascade responsible for myocyte ICAM-1 induction and subsequent neutrophil-induced injury.