Interleukin-18 mediates interleukin-1-induced cardiac dysfunction
Interleukin-18 mediates interleukin-1-induced cardiac dysfunction
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DOI：
10.1152/ajpheart.00795.2013
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发表时间：
2014-04-01
影响因子：
4.8
通讯作者：
Abbate, Antonio
中科院分区：
文献类型：
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作者：
Toldo, Stefano;Mezzaroma, Eleonora;Abbate, Antonio
心力衰竭（HF）患者具有增强的全身IL-1活性，并且在实验小鼠模型中，IL-1诱导左心室（LV）收缩功能障碍。IL-1的作用是直接的还是由诱导细胞因子（如IL-18）介导的，目前尚不清楚。用重组人IL-18结合蛋白（IL-18BP）或IL-18阻断抗体（IL-18AB）中和HF患者血浆或成年雄性小鼠重组鼠IL-1 β后的内源性IL-18。用戊巴比妥钠（30-50 mg/kg）镇静小鼠，测定其血浆IL-18和IL-6 （il -1诱导全身效应的关键介质）水平和左室分数缩短。将IL-18或IL-18受体基因缺失的小鼠与匹配的野生型小鼠进行比较。一组小鼠接受小鼠IL-18治疗，以评估其对左室分数缩短的影响。通过IL-18AB或IL-18BP预处理，可预防HF患者血浆和IL-1 β诱导的左室收缩功能障碍。IL-1 β在IL-18信号基因缺失的小鼠中未能诱导左室收缩功能障碍。IL-1 β诱导血浆IL-18和IL-6水平显著升高。遗传或药理抑制IL-18信号传导未能阻断IL-1 β对IL-6的诱导。综上所述，IL-1诱导小鼠释放活性IL-18介导左室收缩功能障碍，但不诱导IL-6。因此，IL-18阻断可能是治疗心衰的一种新的、更有针对性的治疗方法。
Patients with heart failure (HF) have enhanced systemic IL-1 activity, and, in the experimental mouse model, IL-1 induces left ventricular (LV) systolic dysfunction. Whether the effects of IL-1 are direct or mediated by an inducible cytokine, such as IL-18, is unknown. Recombinant human IL-18-binding protein (IL-18BP) or an IL-18-blocking antibody (IL-18AB) was used to neutralize endogenous IL-18 after challenge with the plasma of patients with HF or with recombinant murine IL-1 beta in adult male mice. Plasma levels of IL-18 and IL-6 (a key mediator of IL-1-induced systemic effects) and LV fractional shortening were measured in mice sedated with pentobarbital sodium (30-50 mg/kg). Mice with genetic deletion of IL-18 or IL-18 receptors were compared with matching wild-type mice. A group of mice received murine IL-18 to evaluate the effects on LV fractional shortening. Plasma from HF patients and IL-1 beta induced LV systolic dysfunction that was prevented by pretreatment with IL-18AB or IL-18BP. IL-1 beta failed to induce LV systolic dysfunction in mice with genetic deletion of IL-18 signaling. IL-1 beta induced a significant increase in plasma IL-18 and IL-6 levels. Genetic or pharmacological inhibition of IL-18 signaling failed to block the induction of IL-6 by IL-1 beta. In conclusion, IL-1 induces a release of active IL-18 in the mouse that mediates the LV systolic dysfunction but not the induction of IL-6. IL-18 blockade may therefore represent a novel and more targeted therapeutic approach to treat HF.