IL-1beta caused pancreatic beta-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.
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.
Wang
Q
Q
Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Ministry of Education, Shanghai Jiaotong University, Shanghai, People's Republic of China. qwangsm@sjth.edu.cn
Zhang
H
H
Zhao
B
B
Fei
H
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000473:pathology; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects; D053583:Interleukin-1beta / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051381:Rats; D019892:eIF-2 Kinase / Q000378:metabolism
D002118:Calcium; D053583:Interleukin-1beta; D048031:JNK Mitogen-Activated Protein Kinases; D019892:eIF-2 Kinase