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The proinflammatory cytokine, IL-1β (Interleukin-1β) is a significant determinant of pancreatic apoptosis and cell death that are common characteristics during diabetes. Using human derived pancreatic MIA PaCa-2 cells, we describe one of the underlying molecular mechanisms behind this observation. Incubation of these cells with IL-1β at doses from 0.5 to 3.0 ng/ml caused significant cell death at 36 h. This was accompanied with marked increases in JNK and p38 phosphorylation together with increased levels of the endoplasmic reticulum (ER) stress markers, namely BiP, CHOP, GADD34, ATF4 and sXBP1. IL-1β also led to increased phosphorylation of eIF2α and all these events could be prevented by pretreatment with the JNK inhibitor, SP600125. A time course study indicated that while IL-1β mediated JNK phosphorylation was induced as early as 2 h of IL-1β treatment, induction of the ER stress …