The antagonist of the JAK-1/STAT-1 signaling pathway improves the severity of cerulein-stimulated pancreatic injury via inhibition of NF-κB activity

Abstract

Abstract. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway is widely involved in cell migration, apoptosis and inflammation. However, its exact mechanisms in severe acute pancreatitis (SAP) remain unclear. The aim of this study was to explore the activity of the JAK/STAT signaling pathway in pancreatic injury, investigate the functional mechanisms of SAP in vitro, and thus elucidate the underlying therapeutic effects for SAP in vivo. The activation of the JAK-1/STAT-1 signaling pathway and the expessions of TNF-α, IL-1β and IL-6 proteins were investigated in AR42J cells induced with cerulein and treated with either PBS, RPM, or AG490. One group of cells was left untreated as a control group. Subsequently the activity of NF-κB was evaluated. Rats were given RPM or AG490 just before the induction of SAP, the severity of which was assessed at 24 h. The findings revealed that the up-regulated expressions of JAK-1/STAT-1, STAT-3 protein were closely correlated with the transcription of TNF-α, IL-1β, and IL-6 in cerulein-stimulated cells. Administration of RPM or AG490 decreased the activity of NF-κB and inhibited the release of TNF-α, IL-1β, and IL-6. The reflective markers of severity of SAP were also decreased by RPM or AG490 treatment compared to SAP rats. This study indicates that the JAK-1/STAT-1 signaling pathway activity is an early event in pancreatic inflammatory injury. Therefore, early treatment with its inhibitors might be beneficial for attenuation of pancreatic injury in SAP. IntroductionSevere acute pancreatitis (SAP) is an inflammatory disease characterized by interstitial edema, vacuolization, acinar necrosis, and inflammatory infiltration of the pancreas. Its high mortality makes SAP a real challenge for clinical treatment (1). Although it has become increasingly clear that the excessive inflammatory response is a determining factor in the process of SAP (2), the exact mechanisms that regulate the severity of SAP remain unclear.The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway is widely involved in cell migration and apoptosis (3). Some studies have shown that the JAK/STAT signaling pathway plays an important role in the inflammatory response. The blockade of the JAK/STAT signaling pathway prevents the lethal effects of the excessive inflammatory response during sepsis (4,5). However, the role of the JAK/STAT signaling pathway in the excessive systemic inflammatory response observed in SAP has not been fully elucidated. In addition, the precise mechanisms determining the effect of the JAK/STAT signaling pathway inhibitors on SAP in relation to the degree of pancreatic injury are largely unclear.AR42J cells are the currently available cell line that shows receptor expression and signal transduction mechanisms parallel to those of normal pancreatic acinar cells. Therefore, AR42J cells have been widely used as an in vitro model to study the secretion, signal transduction, cytoskeleton function, apoptosis and th...

Differential influence of tacrolimus and sirolimus on mitochondrial-dependent signaling for apoptosis in pancreatic cells

“…Conversely, preventive activity against pancreatitis conditions in vivo [12,13] or anti-inflammatory properties have been evidenced [14,15]. Similarly, SIR was confirmed to promote ductal cell loss in vitro [16], but also to protect from acute pancreatitisinducing conditions in vivo and in vitro [17][18][19].…”

Role of Janus Kinase/Signal Transducers and Activators of Transcription in the Pathogenesis of Pancreatitis and Pancreatic Cancer

“…A CCK analogue cerulein triggers phosphorylation of JAK1, STAT1, and STAT3 proteins and induce inflammatory cytokines such as TNF-α, IL-1β, and IL-6 in pancreas 27. CCK receptors are a group of G-protein coupled receptors (GPCRs) which bind two subtypes of CCK, CCK1, and CCK2.…”

“…In pancreatic acinar cells stimulated with TNF-α, the activation of JAK2/STAT3 mediated the development of pancreatic injury 22. Inhibition of JAK/STAT as well as NF-κB improved the severity of pancreatitis 27. Since ROS mediates induction of inflammatory cytokines and NADPH oxidase produces ROS in pancreas, inhibition of NADPH oxidase may be beneficial for the prevention and the treatment of pancreatitis by suppressing JAK2/STAT3 and mitogen activated protein kinases (MAPKs) and expression of TGF-β1 in pancreatic acinar cells 25.…”

“…Although there are reports indicating the involvement of NF-κB in the pathogenesis of pancreatitis and pancreatic cancer, only limited data are available on the role of JAK/STAT in the pathogenesis of these diseases. It has been reported that inhibition of JAK1/STAT1 improves the severity of cerulein-stimulated pancreatic injury by inhibiting NF-κB activation, indicating that activation of JAK1/STAT1 is an early event in pancreatic injury 16. Since JAK/STAT mediates cell proliferation and malignant transformation17 as well as inflammatory signaling18,19 in pancreas, we focus our discussion on the possible role of JAK/STAT in the pathogenesis of pancreatitis and pancreatic cancer in this review.…”

RNA sequence analysis of rat acute experimental pancreatitis with and without fatty liver: a gene expression profiling comparative study

“…Moreover, the excessive activation of JAK/STAT signaling pathway and toll-like receptor signaling pathway was also found in APFL group as shown in heat map. JAK/STAT signaling pathway is involved in the regulation of many inflammatory responses 38 . Toll-like receptor signaling pathway belongs to innate immune responses, which plays an important role in pancreatitis 39, 40 .…”