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

Ji, Yu; Kim, Hye Young

doi:10.5009/gnl.2012.6.4.417

Cited by 50 publications

(35 citation statements)

References 43 publications

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“…Previous studies have demonstrated in several models of acute pancreatitis, including CCK-induced, that there is activation of several important transcriptional factors such as NF-B (25,27,30,56,62), STAT-3 (9,33,62,89), and AP-1 (26,33,62). Our results support the conclusion that, in pancreatic acinar cells, the CCK-induced activation of NF-B, STAT-3, and AP-1 is Src-dependent.…”

Section: Discussionsupporting

confidence: 91%

Src kinases play a novel dual role in acute pancreatitis affecting severity but no role in stimulated enzyme secretion

Nuche-Berenguer

Ramos-Álvarez

Jensen

2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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In pancreatic acinar cells, the Src family of kinases (SFK) is involved in the activation of several signaling cascades that are implicated in mediating cellular processes (growth, cytoskeletal changes, apoptosis). However, the role of SFKs in various physiological responses such as enzyme secretion or in pathophysiological processes such as acute pancreatitis is either controversial, unknown, or incompletely understood. To address this, in this study, we investigated the role/mechanisms of SFKs in acute pancreatitis and enzyme release. Enzyme secretion was studied in rat dispersed pancreatic acini, in vitro acute-pancreatitis-like changes induced by supramaximal COOH-terminal octapeptide of cholecystokinin (CCK). SFK involvement assessed using the chemical SFK inhibitor (PP2) with its inactive control, 4-amino-7-phenylpyrazol[3,4-d]pyrimidine (PP3), under experimental conditions, markedly inhibiting SFK activation. In CCK-stimulated pancreatic acinar cells, activation occurred of trypsinogen, various MAP kinases (p42/44, JNK), transcription factors (signal transducer and activator of transcription-3, nuclear factor-κB, activator protein-1), caspases (3, 8, and 9) inducing apoptosis, LDH release reflective of necrosis, and various chemokines secreted (monocyte chemotactic protein-1, macrophage inflammatory protein-1α, regulated on activation, normal T cell expressed and secreted). All were inhibited by PP2, not by PP3, except caspase activation leading to apoptosis, which was increased, and trypsin activation, which was unaffected, as was CCK-induced amylase release. These results demonstrate SFK activation is playing a dual role in acute pancreatitis, inhibiting apoptosis and promoting necrosis as well as chemokine/cytokine release inducing inflammation, leading to more severe disease, as well as not affecting secretion. Thus, our studies indicate that SFK is a key mediator of inflammation and pancreatic acinar cell death in acute pancreatitis, suggesting it could be a potential therapeutic target in acute pancreatitis.

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Section: Discussionsupporting

confidence: 91%

Src kinases play a novel dual role in acute pancreatitis affecting severity but no role in stimulated enzyme secretion

Nuche-Berenguer

Ramos-Álvarez

Jensen

2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Other studies have also found that immune cells have less responsiveness to type III IFNs [12,32]. However, IL-28A did activate keratinocytes, melanocytes and hepatocytes to induce phosphorylation of STAT1, which is critical for production of inflammatory cytokines such as TNF-a, IL-1b and IL-6 [7,33]. These cytokines may in turn affect T cell polarization.…”

Section: Discussionmentioning

confidence: 85%

Interleukin-28A enhances autoimmune disease in a retinal autoimmunity model

et al. 2014

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“…The Janus kinase 2 (JAK2)/STAT3 pathway is well known to be involved in the immune response of numerous cytokines, including TNF-α and IL-6 (6). In addition, evidence derived from numerous clinical and experimental studies suggests the involvement of the JAK2/STAT3 pathway in pancreatitis (7)(8)(9) or renal diseases (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

Curcumin protects against acute renal injury by suppressing JAK2/STAT3 pathway in severe acute pancreatitis in rats

Zhu

Zhang

Weng

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. The aim of the present study was to investigate the effect of curcumin on acute renal injury in a rat model of severe acute pancreatitis (SAP). A SAP model with acute kidney injury was established in rats by retrograde injection of 5% sodium taurocholate into the pancreatic duct. The serum amylase, creatinine (Cr) and blood urea nitrogen (BUN) levels in rats were measured. Hematoxylin and eosin staining was used to assess pancreatic and renal histological changes. Serum tumor necrosis factor (TNF)-α and interleukin (IL)-6 levels were measured using ELISA kits. Renal protein levels of Janus kinase (JAK) 2/signal transducer and activator of transcription (STAT) 3 pathway components were determined by western blot assay. The results showed that curcumin significantly decreased serum amylase, Cr and BUN levels, and alleviated pancreatic and renal histological changes in SAP rats. Furthermore, curcumin markedly decreased serum TNF-α and IL-6 levels and downregulated renal protein levels of JAK2/STAT3 pathway components. These results proved that curcumin ameliorates acute renal injury in a rat model of SAP. The molecular mechanism of its effect may be associated with the suppression of the JAK2/STAT3 pathway to reduce TNF-α and IL-6 levels in SAP-induced acute renal injury. Therefore, the findings of the present study revealed the potential use of curcumin for the prevention and treatment of SAP and the associated renal injury. IntroductionSevere acute pancreatitis (SAP), an acute inflammatory condition of the pancreas, is considered to be a paradigm of sterile inflammation leading to systemic multiple organ dysfunction syndrome (MODS) and death. Acute renal injury (ARI) is one of the main complications of SAP and significantly increases the mortality rate of patients with AP (66.6 vs. 14.5%) (1). However, the underlying mechanisms of ARI occurring in patients with SAP have remained to be clarified. Increasing evidence has indicated that pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin (IL)-6, have an important role in the pathological mechanisms of SAP and SAP-associated organ failure (2-4). Therefore, inhibiting the transcription and translation of mediators to reduce the secretion of pro-inflammatory factors may ameliorate inflammation and renal failure in SAP.Signal transducers and activators of transcription (STATs), a protein family comprised of seven members (STAT1, -2, -3, -4, -5a, -5b and -6), generally transduce signals from activated receptors or intracellular kinases to the nucleus, thus activating and regulating gene transcription (5). The Janus kinase 2 (JAK2)/STAT3 pathway is well known to be involved in the immune response of numerous cytokines, including TNF-α and IL-6 (6). In addition, evidence derived from numerous clinical and experimental studies suggests the involvement of the JAK2/STAT3 pathway in pancreatitis (7-9) or renal diseases (10-12).Curcumin (diferuloylmethane), the active phytochemical component of turmeric (a spice used mostly in Asia) h...

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

Cited by 50 publications

References 43 publications

Src kinases play a novel dual role in acute pancreatitis affecting severity but no role in stimulated enzyme secretion

Src kinases play a novel dual role in acute pancreatitis affecting severity but no role in stimulated enzyme secretion

Interleukin-28A enhances autoimmune disease in a retinal autoimmunity model

Curcumin protects against acute renal injury by suppressing JAK2/STAT3 pathway in severe acute pancreatitis in rats

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