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

• Published in: Biochemical and biophysical research communications 2018-09, Vol.503 (3), p.1563-1569
• Main Authors: Gu, Liugen, Ge, Zhenming, Wang, Yamin, Shen, Meiqin, Zhao, Ping, Chen, Weichang
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Acute Disease; Acute pancreatitis; Animals; Cells, Cultured; Cerulein; DIGESTIVE SYSTEM DISEASES; Disease Models, Animal; Double-stranded RNA-Dependent kinase (PKR); eIF-2 Kinase - metabolism; INFLAMMATION; Interleukin 6 (IL-6); LACTATE DEHYDROGENASE; LYMPHOKINES; Male; NF-kappa B - metabolism; Nuclear factor kappa B (NF-κB); PANCREAS; Pancreatitis - metabolism; Pancreatitis - pathology; PHOSPHOTRANSFERASES; RATS; Rats, Sprague-Dawley; RNA; RNA, Double-Stranded - metabolism; TRANSCRIPTION FACTORS; Tumor necrosis factor alpha (TNF-α)
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2018.07.080

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.