Regulation of CCAAT/enhancer-binding protein homologous protein (CHOP) expression by interleukin-1 beta in pancreatic beta cells.
Apoptosis contributes to immune-mediated pancreatic beta cell destruction in type I diabetes. Exposure of beta cells to interleukin-1beta (IL-1beta) causes endoplasmic reticulum stress and activates proapoptotic networks. Here, we show that nuclear factor kappaB (NF-kappaB) and mitogen-activated protein kinase (MAPK) signaling pathways regulate the expression of CCAAT/enhancer-binding protein homologous protein (CHOP), which mediates endoplasmic reticulum stress-induced apoptosis. Both CHOP mRNA and protein increase in beta cells treated with IL-1beta. In addition, prolonged exposure to high glucose further increases IL-1beta-triggered CHOP expression. IL-1beta also causes increased expression of C/EBP-beta and a reduction of MafA, NFATc2, and Pdx-1 expression in beta cells. Inhibition of the NF-kappaB and MAPK signaling pathways differentially attenuates CHOP expression. Knocking down CHOP by RNA interference protects beta cells from IL-1beta-induced apoptosis. These studies provide direct mechanistic links between cytokine-induced signaling pathways and CHOP-mediated apoptosis of beta cells.
Shao
Chunli
C
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9041, USA.
Lawrence
Michael C
MC
Cobb
Melanie H
MH
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D015151:Immunoblotting; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D053583:Interleukin-1beta / Q000494:pharmacology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D034622:RNA Interference; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051742:Transcription Factor CHOP / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
C497249:DDIT3 protein, human; D007328:Insulin; D053583:Interleukin-1beta; D016328:NF-kappa B; D014157:Transcription Factors; D051742:Transcription Factor CHOP