JNK1 Deficient Insulin-Producing Cells Are Protected against Interleukin-1 beta-Induced Apoptosis Associated with Abrogated Myc Expression

The relative contributions of the JNK subtypes in inflammatory beta-cell failure and apoptosis are unclear. The JNK protein family consists of JNK1, JNK2, and JNK3 subtypes, encompassing many different isoforms. INS-1 cells express JNK1 alpha 1, JNK1 alpha 2, JNK1 beta 1, JNK1 beta 2, JNK2 alpha 1, JNK2 alpha 2, JNK3 alpha 1, and JNK3 alpha 2 mRNA isoform transcripts translating into 46 and 54 kDa isoform JNK proteins. Utilizing Lentiviral mediated expression of shRNAs against JNK1, JNK2, or JNK3 in insulin-producing INS-1 cells, we investigated the role of individual JNK subtypes in IL-1 beta-induced beta-cell apoptosis. JNK1 knockdown prevented IL-1 beta-induced INS-1 cell apoptosis associated with decreased 46 kDa isoform JNK protein phosphorylation and attenuated Myc expression. Transient knockdown of Myc also prevented IL-1 beta-induced apoptosis as well as caspase 3 cleavage. JNK2 shRNA potentiated IL-1 beta-induced apoptosis and caspase 3 cleavage, whereas JNK3 shRNA did not affect IL-1 beta-induced beta-cell death compared to nonsense shRNA expressing INS-1 cells. In conclusion, JNK1 mediates INS-1 cell death associated with increased Myc expression. These findings underline the importance of differentiated targeting of JNK subtypes in the development of inflammatory beta-cell failure and destruction.