Cardiac macrophage migration inhibitory factor inhibits JNK pathway activation and injury during ischemia/reperfusion.
Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that also modulates physiologic cell signaling pathways. MIF is expressed in cardiomyocytes and limits cardiac injury by enhancing AMPK activity during ischemia. Reperfusion injury is mediated in part by activation of the stress kinase JNK, but whether MIF modulates JNK in this setting is unknown. We examined the role of MIF in regulating JNK activation and cardiac injury during experimental ischemia/reperfusion in mouse hearts. Isolated perfused Mif-/- hearts had greater contractile dysfunction, necrosis, and JNK activation than WT hearts, with increased upstream MAPK kinase 4 phosphorylation, following ischemia/reperfusion. These effects were reversed if recombinant MIF was present during reperfusion, indicating that MIF deficiency during reperfusion exacerbated injury. Activated JNK acts in a proapoptotic manner by regulating BCL2-associated agonist of cell death (BAD) phosphorylation, and this effect was accentuated in Mif-/- hearts after ischemia/reperfusion. Similar detrimental effects of MIF deficiency were observed in vivo following coronary occlusion and reperfusion in Mif-/- mice. Importantly, excess JNK activation also was observed after hypoxia-reoxygenation in human fibroblasts homozygous for the MIF allele with the lowest level of promoter activity. These data indicate that endogenous MIF inhibits JNK pathway activation during reperfusion and protects the heart from injury. These findings have clinical implications for patients with the low-expression MIF allele.
Qi
Dake
D
Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
Hu
Xiaoyue
X
Wu
Xiaohong
X
Merk
Melanie
M
Leng
Lin
L
Bucala
Richard
R
Young
Lawrence H
LH
D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation; D006801:Humans; D066298:In Vitro Techniques; D019746:Intramolecular Oxidoreductases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D008263:Macrophage Migration-Inhibitory Factors; D011971:Receptors, Immunologic; C033184:macrophage migration inhibitory factor receptor; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse