Macrophage migration inhibitory factor induces autophagy to resist hypoxia/serum deprivation-induced apoptosis via the AMP-activated protein kinase/mammalian target of rapamycin signaling pathway.

Abstract

Macrophage migration inhibitory factor (MIF) is an anti‑apoptotic agent in various cell types and protects the heart from stress‑induced injury by modulating autophagy. Autophagy, a conserved pathway for bulk degradation of intracellular proteins and organelles, helps to preserve and recycle energy and nutrients for cells to survive during starvation. The present study hypothesized that MIF protects bone marrow‑derived mesenchymal stem cells (MSCs) from apoptosis by modulating autophagy via the AMP‑activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) signaling pathway. MSCs were obtained from rat bone marrow and cultured. Apoptosis was induced by hypoxia/serum deprivation for 24 h and was assessed using flow cytometry. MIF protected MSCs from apoptosis by modulating autophagy via the AMPK/mTOR signaling pathway resulting in increased expression of autophagy‑associated proteins (including LC3BI/LC3BII, Beclin‑1 and autophagy protein 5), and by increased phosphorylation of AMPK and decreased phosphorylation of mTOR. The MIF anti‑apoptotic effects were blocked by autophagy inhibitor, 3‑methyladenine or AMPK inhibitor, Compound C. These results indicate that MIF exerts a permissive role in protecting MSCs from apoptosis by regulation of autophagy via the AMPK/mTOR signaling pathway.