Role of macrophage migration inhibitory factor in heat‐induced apoptosis in keratinocytes

ABSTRACT In human skin, keratinocytes are constantly challenged by adverse influences, such as hot and cold temperatures; however, the effects of heat on apoptosis induction in keratinocytes are not well understood. Macrophage migration inhibitory factor (MIF) is a potent cytokine that overcomes p53 function by suppressing its transcriptional activity. Here, we evaluated the effects of MIF on hyperthermia (HT)‐induced apoptosis in MIFdeficient [knockout (KO)] and MIF‐transgenic (Tg) mouse keratinocytes. Cells were exposed to HT at 44°C, and increased apoptosis was observed in MIF‐KO and wild‐type (WT) cells compared with MIF‐Tg cells. To determine the mechanism, MIF‐mediated changes in the cellular p53 level and its effects on p53‐dependent death signaling (Bax and p21) and JNK signaling (p‐JNK, JNK, β‐Bad, and Bad) were investigated. MIF‐Tg cells exhibited substantially decreased levels of p53 after HT treatment compared with WT and MIF‐KO cells. In addition, HT treatment caused decreased expression of β‐JNK and β‐Bad in MIF‐Tg cells; however, no such changes were observed in MIF‐KO and WT cells. These results showed that the activation of JNK(p‐JNK and β‐Bad) and p53 may be involved in HT‐induced apoptosis in keratinocytes and that enhanced endogenous MIF expression suppressed apoptosis.—Yoshihisa, Y., Rehman, M. U., Kondo, T., Shimizu, T. Role of macrophage migration inhibitory factor in heat‐induced apoptosis in keratinocytes. FASEB J. 30, 3870–3877 (2016) www.fasebj.org