IL-1β caused pancreatic β-cells apoptosis is mediated in part by endoplasmic reticulum stress via the induction of endoplasmic reticulum Ca2+ release through the c-Jun N-terminal kinase pathway

• DOI: 10.1007/s11010-008-9997-9
• Publication Date: 2009-01-05T18:12:05Z
• Authors: Q. Wang; H. Zhang; B. Zhao; H. Fei
• Keywords: 0301 basic medicine; eIF-2 Kinase; 03 medical and health sciences; Insulin-Secreting Cells; Interleukin-1beta; JNK Mitogen-Activated Protein Kinases; Animals; Apoptosis; Calcium; Endoplasmic Reticulum; Cells, Cultured; Rats

Endoplasmic reticulum (ER) homeostasis is crucial for beta-cell function and survival. Direct as well as indirect evidence has pointed toward Ca(2+) as an important determinant of interleukin-1beta (IL-1beta)-induced beta-cell dysfunction and apoptosis. In the present study, we show that IL-1beta-induced apoptosis and necrosis in primary rat beta-cells and MIN6 cells largely depends on ER stress, ER Ca(2+) release, and c-Jun N-terminal kinase (JNK) activation. beta-cells also showed marked sensitivity to apoptosis induced by sarcoendoplasmic reticulum Ca(2+) ATPase (SERCA) blockers, thapsigargin and cyclopiazonic acid (CPA). IL-1beta induced ER Ca(2+) release, which was paralleled by an IL-1beta-dependent induction of JNK activation and the ER stress response, including activation of PRK (RNA-dependent protein kinase)-like ER kinase (PERK). Furthermore, reduced activation of JNK, utilizing JNK inhibitor SP600125, resulted in significant protection from IL-1beta- or thapsigargin-induced apoptosis via ER stress. In conclusion, our results suggest that the IL-1beta-induced depletion of ER Ca(2+) and activation of the ER stress via JNK pathway are potential contributory mechanisms to beta-cell death.