Selective Inhibition of NF-κB Attenuates the Severity of Cerulein-Induced Acute Pancreatitis

Ethridge, Richard T.; Hashimoto, Koji; Chung, Dai H.; Ehlers, Richard A.; Rajaraman, Srinivasan; Evers, B. Mark

doi:10.1016/s1072-7515(02)01222-x

Cited by 86 publications

(58 citation statements)

References 40 publications

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“…The NBD peptide has been shown to inhibit cytokine-induced NF-B activation and NF-Bdependent gene expression in Hela cells (34), and we previously demonstrated that it blocks LPS-induced MIP-2/CXCL2 gene expression in enterocytes (35). Importantly, the NBD peptide effectively ameliorates inflammation in vivo in models such as ear edema (34), acute peritonitis (induced by intraperitoneal injection of zymosan), and experimental acute pancreatitis (36).…”

Section: Discussionmentioning

confidence: 93%

Inhibition of Nuclear Factor-κB Ameliorates Bowel Injury and Prolongs Survival in a Neonatal Rat Model of Necrotizing Enterocolitis

et al. 2007

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Necrotizing enterocolitis (NEC) is a major cause of morbidity and death in premature infants. NEC is associated with increased levels of pro-inflammatory cytokines in plasma and tissues that are regulated by the transcription factor nuclear factor-B (NF-B). It remains unknown, however, whether NF-B mediates injury in neonatal NEC. We therefore examined the activation status of NF-B perinatally in the small intestine and in a neonatal rat model of NEC. We found that intestinal NF-B is strongly activated at birth and, in dam-fed newborn rats, is down-regulated within a day. In contrast, NF-B remains strongly activated at both d 1 and d 2 in stressed animals, and this is accompanied by a significant decrease in the levels of the endogenous NF-B inhibitor protein IB␣ and IB␤ at d 2. To determine the importance of elevated NF-B activity in intestinal injury in NEC, we administered the NEMO-binding domain (NBD) peptide that selectively inhibits the critical upstream IB kinase (IKK). NBD but not a control peptide decreased mortality and bowel injury in this model, supporting the hypothesis that bowel injury in NEC results from elevated NF-B activity. Our findings therefore lead us to conclude that selective NF-B inhibition represents a promising therapeutic strategy for NEC.

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Section: Discussionmentioning

confidence: 93%

Inhibition of Nuclear Factor-κB Ameliorates Bowel Injury and Prolongs Survival in a Neonatal Rat Model of Necrotizing Enterocolitis

et al. 2007

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“…However, it largely attenuated cerulein-induced IKK2 kinase activity in vitro and ameliorated the course of acute, cerulein-induced edematous pancreatitis in vivo. Earlier experiments using pharmacological inhibitors of NF-κB showed downregulation of chemokine expression and an attenuation of acute, cerulein-induced pancreatitis in vivo (16,(23)(24)(25). However, conflicting results were found with the use of pharmacological inhibitors of NF-κB in the cerulein model.…”

Section: Discussionmentioning

confidence: 99%

Constitutive IKK2 activation in acinar cells is sufficient to induce pancreatitis in vivo

Baumann¹,

Wagner²,

Aleksic³

et al. 2007

J. Clin. Invest.

113

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Activation of the inhibitor of NF-κB kinase/NF-κB (IKK/NF-κB) system and expression of proinflammatory mediators are major events in acute pancreatitis. However, the in vivo consequences of IKK activation on the onset and progression of acute pancreatitis remain unclear. Therefore, we modulated IKK activity conditionally in pancreatic acinar cells. Transgenic mice expressing the reverse tetracycline-responsive transactivator (rtTA) gene under the control of the rat elastase promoter were generated to mediate acinar cell-specific expression of IKK2 alleles. Expression of dominant-negative IKK2 ameliorated cerulein-induced pancreatitis but did not affect activation of trypsin, an initial event in experimental pancreatitis. Notably, expression of constitutively active IKK2 was sufficient to induce acute pancreatitis. This acinar cell-specific phenotype included edema, cellular infiltrates, necrosis, and elevation of serum lipase levels as well as pancreatic fibrosis. IKK2 activation caused increased expression of known NF-κB target genes, including mediators of the inflammatory response such as TNF-α and ICAM-1. Indeed, inhibition of TNF-α activity identified this cytokine as an important effector of IKK2-induced pancreatitis. Our data identify the IKK/NF-κB pathway in acinar cells as being key to the development of experimental pancreatitis and the major factor in the inflammatory response typical of this disease. IntroductionThe NF-κB transcription factors play a prominent role in controlling the integration of innate immunity into the inflammatory response and adaptive immunity. The activation and nuclear translocation of NF-κB induces the expression of a diverse range of proinflammatory genes, including chemokines, cytokines, and cell adhesion molecules, all necessary for an effective defense response to infectious agents. However, failure to terminate or resolve the inflammatory response has detrimental consequences for the organism. As NF-κB is one of the main transcriptional regulators of inflammation, pathological activation of NF-κB is often associated with chronic inflammatory diseases like rheumatoid arthritis, inflammatory bowel disease, asthma, and multiple sclerosis (1-3).NF-κB represents a family of homodimeric and heterodimeric transcription factors composed of 5 members, namely p50, p52, RelA/p65, RelB, and c-Rel. NF-κB is activated by a large number of inducers, including factors critically involved in the inflammatory response such as TNF-α, IL-1β, and microbial products. These factors activate the TNF, IL-1, Nod-like, and Toll-like receptor systems and thereby initiate signaling cascades that converge on the classical NF-κB pathway. This induces the nuclear translocation of NF-κB dimers typically composed of p50 and RelA/p65. The pivotal regulatory step in this pathway is the signal-induced phosphorylation of inhibitor of NF-κB (IκB) proteins, which are mediated by the IκB kinase (IKK) complex. In unstimulated cells, IκB proteins interact with the NF-κB proteins and inhibit their nuclear translo...

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“…NF-κB and p38 MAPK are the most studied signaling molecules in this regard and their relevance to such disease states has been established primarily through the use of inhibitors. Indeed, selective inhibition of NF-κB and p38 MAP kinase inhibitors has demonstrated efficacy in a variety of animal models [36][37][38][39][40] . Specific p38 inhibitors and selective inhibition of NF-κB aimed at reducing the production of inflammatory mediators are now being developed, and might in the future provide more effective treatment for inflammatory diseases.…”

Section: Discussionmentioning

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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Selective Inhibition of NF-κB Attenuates the Severity of Cerulein-Induced Acute Pancreatitis

Cited by 86 publications

References 40 publications

Inhibition of Nuclear Factor-κB Ameliorates Bowel Injury and Prolongs Survival in a Neonatal Rat Model of Necrotizing Enterocolitis

Inhibition of Nuclear Factor-κB Ameliorates Bowel Injury and Prolongs Survival in a Neonatal Rat Model of Necrotizing Enterocolitis

Constitutive IKK2 activation in acinar cells is sufficient to induce pancreatitis in vivo

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

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