David WHITE，GAO Xiao-ming，William CHAM，Andrew TAYLOR，Stephen DUFFY，Anthony DART，DU Xiao-Jun△

(1Experimental Cardiology Laboratory，Baker IDI Heart and Diabetes Institute，2Alfred Heart Centre，Alfred Hospital，Melbourne，Victoria 3004，Australia)

AIM:The pro-inflammatory cytokine macrophage migration-inhibitory factor(MIF)is known to play a key role in a number of inflammatory diseases. However，its change in the setting of acute myocardial infarct (MI)and significance in activating innate immune response remain unexplored.METHODS:Using the mouse model of MI，we studied the changes of cardiac and circulating MIF(by ELISA)in C57BL/6 mice and the phenotype of post-MI inflammatory response of MIF-knockout (MIF KO)mice (in C57BL/6 background). Clinically，we investigated regulation of MIF in peripheral blood mononuclear cells (PBMC)from patients with acute MI or healthy controls. Relationship between plasma MIF levels (by ELISA)and infarct size (IS，determined by histology in mice or magnetic resonance imaging，MRI，in patients)was analyzed.RESULTS:MI within 1 h in mice led to a rapid and partial depletion of cardiac MIF content. There was a simultaneous increase by up to 3 -fold plasma MIF concentration，which was highly correlated with IS，indicating cardiac release of MIF. In mice with global MIF KO or chimeric mice with MIF expression only by hematopoietic cells，post -infarct inflammatory responses，measured as immune cell infiltration and expression of inflammatory mediators，were blunted，indicating that cardiac MIF release acts as an initiator of post-infarct innate immunity. Cultured human PBMC were activated by treatment with MIF measured by enhanced expression of matrix metalloproteinases (MMP-9)and interleukins (IL-1β，IL-6). PBMC from patients with acute MI showed lack of activation at 3 h after MI. By 72 h after MI，however，PBMC showed heightened expression of inflammatory molecules，which was abolished by anti-MIF interventions，further supporting MIF as a mediator of inflammatory response after MI.Patients with confirmed ST-elevation MI showed that 72% of cases had elevated MIF levels over the upper-limit of healthy controls or stable angina patients，in the first attainable blood sample after admission，when other biomarkers were elevated in less than 30% of patients. Significant correlation was observed between the first obtainable plasma MIF levels and IS in mice or in patients with acute MI. Admission MIF levels also significantly correlated with ventricular chamber size and the degree of ventricular dysfunction determined by MRI at 3 days or 3 months after acute MI.CONCLUSION:Cardiac release of MIF upon acute ischemia and infarction functions as a key danger signal activating innate immune response. Based on a single assay at the time of hospital admission，MIF is a useful new biomarker for confirmation of MI diagnosis，prediction of IS and estimation of inflammatory response.

* ［Foundation item］National Health and Medical Research Council of Australia

△Corresponding author E-mail:Xiao-jun.du@bakeridi.edu.au