Dhanantwari Preeta, Nadaraj Sumekala, Kenessey Agnes, Chowdhury Devyani, Al-Abed Yousef, Miller Edmund J, Ojamaa Kaie
Division of Pediatric Cardiology, Schneider Children's Hospital, North Shore Long Island Jewish Health System, 76th Avenue, New Hyde Park, NY, USA.
Biochem Biophys Res Commun. 2008 Jun 27;371(2):298-303. doi: 10.1016/j.bbrc.2008.04.070. Epub 2008 Apr 24.
Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that causes cardiac contractile dysfunction, whereas inactivation of MIF improves cardiac function in experimental animal models of sepsis. We used cultured cardiomyocytes to determine whether MIF-induced contractile dysfunction was mediated in part by myocyte apoptosis and to identify MIF-activated intracellular signaling pathways in this process. MIF treatment significantly increased myocyte apoptosis in a dose-dependent manner to 15.5+/-3.9% and 26.0+/-7.1% TUNEL positive nuclei (20 and 30 ng/ml MIF for 24h) vs control (3.7+/-0.9%). This effect was attenuated by inactivation of MIF with the chemical inhibitor, ISO-1. MIF-induced cleavage of caspase 3 and reduction of Bcl-xL/Bax were similarly attenuated by ISO-1 pre-treatment. MIF stimulated the rapid, transient phosphorylation of stress kinases, p38MAPK and JNK. Thus, MIF induces cardiomyocyte apoptosis by activating stress kinases and mitochondria-associated apoptotic mechanisms, whereas inactivation of MIF pro-inflammatory activity improves cardiomyocyte survival.
巨噬细胞移动抑制因子（MIF）是一种促炎细胞因子，可导致心脏收缩功能障碍，而在脓毒症实验动物模型中，MIF失活可改善心脏功能。我们使用培养的心肌细胞来确定MIF诱导的收缩功能障碍是否部分由心肌细胞凋亡介导，并确定在此过程中MIF激活的细胞内信号通路。MIF处理以剂量依赖的方式显著增加心肌细胞凋亡，TUNEL阳性细胞核分别为15.5±3.9%和26.0±7.1%（20和30 ng/ml MIF处理24小时），而对照组为3.7±0.9%。用化学抑制剂ISO-1使MIF失活可减弱这种效应。ISO-1预处理同样减弱了MIF诱导的半胱天冬酶3裂解以及Bcl-xL/Bax的减少。MIF刺激应激激酶p38MAPK和JNK快速、短暂地磷酸化。因此，MIF通过激活应激激酶和线粒体相关凋亡机制诱导心肌细胞凋亡，而MIF促炎活性的失活可提高心肌细胞存活率。
