Cardiac macrophage migration inhibitory factor inhibits JNK pathway activation and injury during ischemia/reperfusion

Abstract

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.

A Novel Allosteric Inhibitor of Macrophage Migration Inhibitory Factor (MIF)

“…Elevated circulating levels of MIF have been observed in rheumatoid arthritis, atherosclerosis, asthma, lupus, diabetes, colitis, sepsis, cancer, and cardiovascular and infectious diseases (15)(16)(17)(18)(19)(20). Genetic evidence further supports the involvement of MIF in disease.…”

Soluble CD74 Reroutes MIF/CXCR4/AKT‐Mediated Survival of Cardiac Myofibroblasts to Necroptosis

“…Cardioprotection by MIF is mediated through its intrinsic antioxidant capacity and by signaling through its cognate receptor CD74, a type II transmembrane glycoprotein and the surface form of class II invariant chain 25, 26, 27, 28, 29, 30, 31. In fact, The MIF/CD74/AMPK (adenosine monophosphate kinase) signaling pathway has repeatedly been demonstrated to play a pivotal protective role in acute myocardial ischemia/reperfusion injury 31, 32, 33.…”

“…In fact, The MIF/CD74/AMPK (adenosine monophosphate kinase) signaling pathway has repeatedly been demonstrated to play a pivotal protective role in acute myocardial ischemia/reperfusion injury 31, 32, 33. MIF also signals through the chemokine receptors, C‐X‐C chemokine receptor (CXCR)2 and CXCR4,34 and has been found to exhibit compartmentalized protective and detrimental effects through CXCR2 receptor in a mouse model of myocardial ischemia/reperfusion 35.…”

4-IPP, a selective MIF inhibitor, causes mitotic catastrophe in thyroid carcinomas

“…These functions have been previously reported in other studies. MIF stimulates heart muscle glucose uptake, and the autocrine/paracrine effects of endogenous cardiac MIF contribute to AMPK activation and glucose uptake during ischemia (Qi et al 2009). Thus, AMPK is considered a type of cardioprotective stress kinase (Russell et al 2004), and the action of MIF modulation of AMPK is beneficial during ischemia.…”