Chandrasekar Bysani, Colston James T, de la Rosa Sam D, Rao Perla P, Freeman Gregory L
Department of Medicine/Cardiology, University of Texas Health Science Center, San Antonio 78229, USA.
Biochem Biophys Res Commun. 2003 Apr 18;303(4):1152-8. doi: 10.1016/s0006-291x(03)00496-0.
Myocardial ischemia/reperfusion is characterized by oxidative stress and induction of proinflammatory cytokines. Interleukin (IL)-18, a member of the IL-1 family, acts as a proinflammatory cytokine, and is induced during various immune and inflammatory disorders. Therefore, in the present study we investigated whether IL-18 expression is regulated by cytokines and oxidative stress in cardiomyocytes. TNF-alpha induced rapid and sustained activation of NF-kappaB whereas H(2)O(2) induced delayed and transient activation. Both TNF-alpha and H(2)O(2) induced IL-18 mRNA and precursor protein in cardiomyocytes, and IL-18 release into culture supernatants. However, only TNF-alpha led to sustained expression. Expression of IL-18Rbeta, but not alpha, was induced by both agonists. TNF-alpha and H(2)O(2) induced delayed expression of IL-18 BP. Pretreatment with PDTC attenuated TNF-alpha and H(2)O(2) induced IL-18 and IL-18Rbeta, but not basal expression of IL-18Ralpha. These results indicate that adult cardiomyocytes express IL-18 and its receptors, and proinflammatory cytokines and oxidative stress regulate their expression via activation of NF-kappaB. Presence of both ligand and receptors suggests IL-18 impacts myocardial biology through an autocrine pathway.
心肌缺血/再灌注的特征是氧化应激和促炎细胞因子的诱导。白细胞介素（IL）-18是IL-1家族的成员，作为一种促炎细胞因子，在各种免疫和炎症性疾病中被诱导产生。因此，在本研究中，我们调查了心肌细胞中IL-18的表达是否受细胞因子和氧化应激的调节。肿瘤坏死因子-α（TNF-α）诱导核因子-κB（NF-κB）快速且持续的激活，而过氧化氢（H₂O₂）诱导延迟且短暂的激活。TNF-α和H₂O₂均诱导心肌细胞中IL-18 mRNA和前体蛋白的表达，并促使IL-18释放到培养上清液中。然而，只有TNF-α导致持续表达。两种激动剂均诱导IL-18Rβ而非IL-18Rα的表达。TNF-α和H₂O₂诱导IL-18结合蛋白（IL-18 BP）延迟表达。用吡咯烷二硫代氨基甲酸盐（PDTC）预处理可减弱TNF-α和H₂O₂诱导的IL-18和IL-18Rβ表达，但不影响IL-18Rα的基础表达。这些结果表明，成年心肌细胞表达IL-18及其受体，促炎细胞因子和氧化应激通过激活NF-κB调节它们的表达。配体和受体的存在表明IL-18通过自分泌途径影响心肌生物学。
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