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

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 inMIF-KO and wild-Type (WT) cells compared withMIF-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, p-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 p-JNK and p-Bad in MIF-Tg cells; however, no such changes were observed inMIF-KOandWTcells. These results showed that the activation of JNK(p-JNKand p-Bad) and p53may be involved in HT-induced apoptosis in keratinocytes and that enhanced endogenous MIF expression suppressed apoptosis.