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Double-stranded RNA-dependent kinase PKR activates NF-κB pathway in acute pancreatitis

Author:
Gu, Liugen, Ge, Zhenming, Wang, Yamin, Shen, Meiqin, Zhao, Ping, Chen, Weichang
Source:
Biochemical and biophysical research communications 2018 v.503 no.3 pp. 1563-1569
ISSN:
0006-291X
Subject:
IKappaB kinase, inflammation, interleukin-6, lactate dehydrogenase, models, pancreatitis, phosphorylation, rats, tissues, transcription factor NF-kappa B, trypsinogen, tumor necrosis factor-alpha
Abstract:
The activation of transcription factor nuclear factor kappa B (NF-κB) occurs early in acute pancreatitis (AP) simultaneously with intracellular trypsinogen activation. Double-stranded RNA-dependent kinase (PKR) promotes the activation of NF-κB and the production of pro-inflammatory factors including tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6). The rat and rat pancreatic AR42J cells were treated by cerulein to establish AP models, showing PKR increased. TNF-α, IL-6 and lactate dehydrogenase (LDH) in AP pancreatic tissues and cerulein-treated AR42J cells increased, while PKR knockdown in AR42J cells reversed cerulein-induced inflammatory response and pancreatic cell injury. In addition, inhibitor of kappa B kinase α (IKKα), phosphorylated P65 (p-P65), P65 increased in cerulein-treated AR42J cells. Meanwhile, in cerulein-treated AR42J cells, interaction between PKR and IKKα, as well as the co-localization and nuclear accumulation of PKR and P65, were detected. Furthermore, cerulein induced the phosphorylation and nuclear translocation of P65, which indicated the activation of NF-κB, while PKR knockdown hindered NF-κB activation to alleviate pancreatic cell injury. In summary, PKR might promote NF-κB activation via facilitating its phosphorylation and nuclear translocation, thus accelerated inflammatory response and pancreatic cell injury in AP, implying a novel molecular target for the treatment of AP.
Agid:
6093146