Macrophage migration inhibitory factor induces cardiomyocyte apoptosis
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- 作者：Preeta Dhanantwari ; Sumekala Nadaraj ; Agnes Kenessey ; Devyani Chowdhury ; Yousef Al-Abed ; Edmund J. Miller ; Kaie Ojamaa
- 关键词：MIF ; ISO-1 ; Cytokines ; Apoptosis ; Aardiomyocyte ; Macrophage migration inhibitory factor ; JNK ; p38MAPK ; ERK ; Caspase 3 ; Bcl-xL/Bax
- 刊名：Biochemical and Biophysical Research Communications
- 出版年：2008
- 出版时间：27 June 2008
- 年：2008
- 卷：371
- 期：2
- 页码：298-303
- 全文大小：574 K
文摘
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 24 h) 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.