Acute experimental pancreatitis and NF-κB/rel activation

Algül, Hana; Tando, Yusuke; Schneider, Günter; Weidenbach, H; Adler, Guido; Schmid, Roland M.

doi:10.1159/000066090

Cited by 76 publications

(64 citation statements)

References 46 publications

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“…The role of NF-B in pancreatitis is currently a subject of considerable controversy. Although it is generally believed that NF-B activation in the pancreas triggers proinflammatory events (24,25), some studies (26,27) have suggested that NF-B activation may trigger anti-inflammatory responses. Our observation (a) that Tpl2 ablation interferes with pancreatic inflammation but not pancreatic injury/necrosis and (b) that Tpl2 ablation does not alter secretagogue-induced NF-B translocation to the nucleus during pancreatitis might suggest that NF-B functions primarily as a mediator of events leading to pancreatic injury/necrosis rather than inflammation.…”

Section: Discussionmentioning

confidence: 99%

Tumor Progression Locus-2 Is a Critical Regulator of Pancreatic and Lung Inflammation during Acute Pancreatitis

Acker

Perides

Weiss

et al. 2007

Journal of Biological Chemistry

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Pancreatic and lung inflammation during acute pancreatitis is a poorly understood, but clinically important, phenomenon. The proto-oncogene Tpl2 (tumor progression locus-2) has recently been shown to have important immunomodulatory effects on some inflammatory processes, but its importance to pancreatitis has not been previously examined. Our studies were designed to (a) define the effects of Tpl2 on pancreatic and lung inflammation during pancreatitis and (b) identify mechanisms and cell types responsible for those effects. We examined pancreatitis-associated Tpl2 effects in wild type and Tpl2 ؊/؊ mice subjected to either secretagogue-induced or bile salt-induced pancreatitis. To determine the myeloid or non-myeloid lineage of cells responsible for the Tpl2 effects, we used Tpl2 ؊/؊ chimeric mice generated by lethal irradiation followed by bone marrow transplantation. Mechanisms responsible for the effects of Tpl2 ablation on caerulein-induced proinflammatory events were evaluated under in vivo and in vitro conditions using the techniques of electrophoretic mobility shift assay, immunoblot analysis, and quantitative reverse transcription-PCR. We found that Tpl2 ablation markedly reduced pancreatic and lung inflammation in these two dissimilar models of pancreatitis, but it did not alter pancreatic injury/necrosis in either model. The reduction in caerulein-induced pancreatic inflammation is dependent upon Tpl2 ablation in non-myeloid cells and is associated with both in vivo and in vitro inhibition of MEK, JNK, and AP-1 activation and the expression of MCP-1, MIP-2, and interleukin-6. Non-myeloid cell expression of Tpl2 regulates pancreatic inflammation during pancreatitis by mediating proinflammatory signals and the generation of neutrophil chemoattracting factors.Severe acute pancreatitis is a devastating disease associated with considerable morbidity and with mortality rates that can reach or exceed 20%. Most of the early deaths during severe pancreatitis are the result of inflammation-related complications including the systemic immune response syndrome and/or pancreatitis-associated lung injury, which clinically presents as the adult respiratory distress syndrome. The events responsible for regulating the inflammatory response in acute pancreatitis, and for coupling pancreatic injury with lung injury, are poorly understood but are of considerable clinical importance because interventions that prevent or limit those responses are likely to reduce the morbidity and mortality of the disease.Tpl2 is a proto-oncogene that has been shown to function as a MAP3K (mitogen-activated protein kinase kinase kinase) and, in this way, to play critical roles in certain inflammatory conditions. We now report the first studies that have examined the possible immunomodulatory effects of Tpl2 in acute pancreatitis. The results of our studies lead us to conclude that Tpl2 acts as a critical regulator of pancreatitis-associated inflammation by mediating the induction of chemoattracting chemokines and that it is Tpl2 expressed b...

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Section: Discussionmentioning

confidence: 99%

Tumor Progression Locus-2 Is a Critical Regulator of Pancreatic and Lung Inflammation during Acute Pancreatitis

Acker

Perides

Weiss

et al. 2007

Journal of Biological Chemistry

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“…For example, recent evidence strongly suggested the crucial role of NF-κB in the initiation of AP, not only in pancreatic acinar cells and monocytes/macrophages but also in specific distant organs, such as the lung. NF-κB is able to mediate a variety of inflammatory mediators involved in AP, including cytokines and adhesion molecules, as well as specific inducible isoform of nitric oxide synthase enzymes [12][13][14][15][16][17][18][19][20][21] . Additionally, recent evidence has also shown the contribution of p38 MAP kinase to the mechanism underlying cytokine expression in pancreatic acinar cells and monocytes/ macrophages.…”

Section: Introductionmentioning

confidence: 99%

Effect of NF-κB and p38 MAPK in activated monocytes/macrophages on pro-inflammatory cytokines of rats with acute pancreatitis

Liu¹,

Pan²,

Liu³

et al. 2003

WJG

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AIM: Proinflammatory cytokines TNF-α and IL-6 play a main role in acute pancreatitis (AP). Cytokine biosynthesis runs through two major signaling pathways at the level of proteins: nuclear transcription factor-κB (NF-κB) and p38 mitogen-activated protein kinase (p38 MAPK). The aim of the study was to investigate the effect of NF-κB and p38 MAPK in activated monocytes/macrophages on cytokines of rats with acute pancreastitis. METHODS:Taurocholate (3 % and 5 %) at doses of 1 mL/kg was administered into the biliopancreatic duct of male Sprague-Dawley (SD) rats to reduce acute edematous pancreariris (AEP) and acute necrotizing pancreatitis (ANP). Pancreatic tissues were prepared immediately after death. At this point, blood was obtained for determination of serum amylase and pro-inflammatory TNF-α and IL-6. Activated monocytes/macrophages were captured from blood and so were ascites. NF-κB and p38 MAPK in activated monocytes/ macrophages were measured by immunohistochemistry method. Pancreatic tissue samples were prepared for routine light microscopy, using hematoxylin and eosin (HE) staining. RESULTS:The serum levels of amylase were 3 056.00± 1 232.35 IU/L and 4 865.12±890.34 IU/L at 3 and 6 hours in ANP group, which were significantly higher than those (3 056.00±1 232.35 IU/L and 3 187.17±821.16 IU/L) (P<0.05, respectively) in AEP group. In ascites the levels were 3.32±1.01 g and 3.76±1.12 g at 3 and 6 hours in ANP group, which were significantly higher than those (1.43±1.02 g and 2.56±1.21 g) (P<0.05, respectively) in AEP group. The serum levels of TNF-α were 54.27±23.48 pg/ml and 67.83±22.02 pg/ml in AEP group and 64.28±20.79 pg/ml and 106.59± 43.71 pg/ml in ANP group, and the serum levels of IL-6 were 428.12±140.30 pg/ml and 420.13±139.40 pg/ml in AEP group and 1 600.32±309.78 pg/ml and 2 203.76±640.85 pg/ml in ANP group, which were far significantly higher than those in sham group (P<0.001, respectively). The serum level of TNF-α 6 hours after establishment of the studied model and that of IL-6 at 3 and 6 hours in ANP group were significantly higher than those in AEP (P<0. 05, P<0.001, P<0.05). In ANP group, the levels of serum TNF-α and IL-6 6 hours after establishment of the studied model were significantly higher than those 3 hours after establishment of studied model (P<0.05, P<0.05, respectively). Three and 6 hours after establishment of the model, typical pathological changes of AEP and ANP were found,

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“…The close correlation between the NF-B expression and the extent of inflammation was reported in SAP by related studies, the results of which suggest that NF-B could be a major inflammatory regulating factor in SAP (28). However, little is known about the relationship between the role of NF-B and of the JAK-1/STAT-1 signaling pathway in the regulation of the systemic inflammatory response during SAP.…”

Section: Discussionmentioning

confidence: 80%

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

Chen

Huang²,

Zhang³

et al. 2011

Int J Mol Med

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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...

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Acute experimental pancreatitis and NF-κB/rel activation

Cited by 76 publications

References 46 publications

Tumor Progression Locus-2 Is a Critical Regulator of Pancreatic and Lung Inflammation during Acute Pancreatitis

Tumor Progression Locus-2 Is a Critical Regulator of Pancreatic and Lung Inflammation during Acute Pancreatitis

Effect of NF-κB and p38 MAPK in activated monocytes/macrophages on pro-inflammatory cytokines of rats with acute pancreatitis

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

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