The c-Jun amino-terminal kinase pathway is preferentially activated by interleukin-1 and controls apoptosis in differentiating pancreatic beta-cells

To characterize the differentiation events that selectively target insulin- producing cells to interleukin (IL)1 beta-induced apoptosis, we studied IL- 1 beta signaling via mitogen-activated protein kinase (MAPK) and stress-act ivated protein kinase in 2 pancreatic endocrine cell lines. We studied the glucagon-secreting AN-glu cell line and the insulin and the islet amyloid p olypeptide-producing beta-cell line (AN-ins cells), which is derived by sta ble transfection of AN-glu cells with the transcription factor pancreatic d uodenal homeobox factor-1. AN-ins cells were more sensitive to the cytotoxi c action of IL-1 beta, This increased sensitivity was not associated with a more pronounced IL-1-induced nitric oxide production in AN-ins cells, but it correlated with a more marked activation of the 3 MAPKs extracellular si gnal-regulated kinases (ERKs)-1/2, c-Jun NH2-terminal kinase (JNK), and p38 MAPK (p38), This led to increased phosphorylation of the transcription fac tors c-Jun, Elk-1, and ATF2 and of heat shock protein 25, Inhibition of ERK -1/2 and p38 did not prevent but aggravated IL-1 beta-induced cell death. I n contrast, inhibition of JNK by transfection with the dominant negative in hibitor of the JNK-binding domain prevented apoptosis in both cell types. C ell death could be elicited by overexpressing the catalytic domain of MAPK kinase kinase 1, a specific activator of JNK and nuclear factor-kappa B, wh ich does not recruit ERK-1/2 or p38, Coactivation of ERK-1/2 with JNK did n ot prevent apoptosis, In conclusion, increased MAPK signaling in response t o IL-1 beta may represent a novel molecular marker of beta-cell differentia tion. JNK inhibition represents an effective means of preventing IL-1 beta- activated beta-cell destruction.