Takahashi M, Nishihira J, Shimpo M, Mizue Y, Ueno S, Mano H, Kobayashi E, Ikeda U, Shimada K
Division of Cardiology, Jichi Medical School, Tochigi, Japan.
Cardiovasc Res. 2001 Dec;52(3):438-45. doi: 10.1016/s0008-6363(01)00408-4.
Macrophage migration inhibitory factor (MIF), which plays a pivotal role in the control of inflammatory responses, was first characterized as a T-cell cytokine, but later was also found as a pituitary peptide released in response to infection and stress. However, MIF's role and expression in the myocardium has never been reported. The goal of this study is to examine MIF in the myocardium.
MIF protein and mRNA levels were assayed using enzyme-linked immunosorbent assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR), respectively. Increased MIF concentrations were detected in the sera of patients with acute myocardial infarction (AMI). In cultured rat cardiac myocytes, significant amounts of MIF were produced in response to hypoxia and hydrogen peroxide (H(2)O(2)), but not to angiotensin II, endothelin-1, interleukin-1beta (IL-1beta) or tumor necrosis factor alpha (TNFalpha). H(2)O(2)-induced MIF production increased in a time- and dose-dependent manner and was completely abolished in the presence of catalase. H(2)O(2) also induced MIF mRNA expression. The H(2)O(2)-induced MIF production was completely inhibited by the protein kinase C (PKC) inhibitor GF109203X, partially inhibited by the tyrosine kinase inhibitor herbimycin A, and uninhibited by calcium chelation or phorbol ester-sensitive PKC down-regulation. This suggests that H(2)O(2)-induced MIF production is mediated by an atypical PKC isoform. DNA microarray analysis revealed that 52 genes were preferentially expressed in response to MIF. Of these, the MIF-induced expression of both glutathione S-transferase (GST) and lipopolysaccharide-induced CXC chemokine (LIX) mRNAs was confirmed using RT-PCR analysis.
The present results suggest that MIF is expressed by the myocardium in response to redox stress and may play a role in the pathogenesis of myocardial ischemia.
巨噬细胞移动抑制因子（MIF）在炎症反应控制中起关键作用，最初被鉴定为一种T细胞细胞因子，但后来也被发现是一种在感染和应激时释放的垂体肽。然而，MIF在心肌中的作用和表达从未被报道过。本研究的目的是检测心肌中的MIF。
分别采用酶联免疫吸附测定（ELISA）和逆转录-聚合酶链反应（RT-PCR）检测MIF蛋白和mRNA水平。在急性心肌梗死（AMI）患者的血清中检测到MIF浓度升高。在培养的大鼠心肌细胞中，缺氧和过氧化氢（H₂O₂）可诱导产生大量MIF，但血管紧张素II、内皮素-1、白细胞介素-1β（IL-1β）或肿瘤坏死因子α（TNFα）则不能。H₂O₂诱导的MIF产生呈时间和剂量依赖性增加，并且在过氧化氢酶存在时完全被抑制。H₂O₂也诱导MIF mRNA表达。H₂O₂诱导的MIF产生被蛋白激酶C（PKC）抑制剂GF109203X完全抑制，被酪氨酸激酶抑制剂赫司特霉素A部分抑制，而钙螯合或佛波酯敏感的PKC下调则对其无抑制作用。这表明H₂O₂诱导的MIF产生是由一种非典型PKC亚型介导的。DNA微阵列分析显示，有52个基因在MIF作用下优先表达。其中，谷胱甘肽S-转移酶（GST）和脂多糖诱导的CXC趋化因子（LIX）mRNA的MIF诱导表达通过RT-PCR分析得到证实。
目前的结果表明，MIF在心肌中因氧化还原应激而表达，可能在心肌缺血的发病机制中起作用。
