Kinetic study of TNF‐α production and its regulatory mechanisms in acinar cells during acute pancreatitis induced by bile–pancreatic duct obstruction

Ramudo, Laura; Manso, Manuel A.; Sevillano, Sara; Dios, Isabel De

doi:10.1002/path.1747

Cited by 56 publications

(43 citation statements)

References 43 publications

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“…Studies have shown TNF-␣ to inhibit eNOS expression in various cell types [36,37] by interfering with the association of sp1 and sp3 to the upstream promoter site of eNOS. Though this has not been directly shown in pancreatic acinar cells it is possible to speculate, as TNF-␣ has been shown to be expressed in the pancreas as well as in pancreatic acinar cells in response to AP [38,39] . It may be argued that the overproduction of NO by iNOS may compensate for the reduction in eNOS expression, thus conferring the protection associated with NO and leukocyte adhesion [34,35] .…”

Section: Discussionmentioning

confidence: 99%

Expression of Nitric Oxide Synthase Isoforms and Nitric Oxide Production in Acute Pancreatitis and Associated Lung Injury

Ang

Adhikari

et al. 2009

Pancreatology

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Section: Discussionmentioning

confidence: 99%

Expression of Nitric Oxide Synthase Isoforms and Nitric Oxide Production in Acute Pancreatitis and Associated Lung Injury

Ang

Adhikari

et al. 2009

Pancreatology

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“…The role of TNF-α, a proinflammatory cytokine, is well recognized in experimental pancreatitis models (15,(38)(39)(40). TNF-α receptor-deficient mice develop less severe pancreatitis in response to cerulein hyperstimulation (ref.…”

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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“…Pentoxiphylline [23] , cyclooxygenase inhibitors [24] , allopurinol [20] , octreotide [25] are various agents used in experimental studies to overcome these oxidative insults and cytokine-related injury. In this study, pancreatitis was induced in rats with 2 intraperitoneal doses of cerulein, and diluted MMF (Cellcept 500 Group Studies on experimental models of pancreatitis have shown the presence of inflammatory cytokines in the sera of subjects [26,27] . We now know that these cytokines appear within 30 min after the induction of acute pancreatitis, before the appearance of histopathological changes in the pancreatic parenchyma.…”

Section: Discussionmentioning

confidence: 99%

Effect of Mycophenolate Mofetil on Cerulein-Induced Acute Pancreatitis

Taşdoğan¹,

Kucuk²,

Kurt³

et al. 2010

Eur Surg Res

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Aim: The aim of this study was to determine the effects of mycophenolate mofetil (MMF) on acute pancreatitis with evaluation of biochemical and histopathological findings. Materials and Methods: Cerulein was administered to induce acute pancreatitis in rats. Three groups of 10 rats each were formed. Animals in group 1 received physiologic saline solution. In group 2 animals received MMF at a dose of 14 mg/kg and group 3 had double doses of MMF. Alanine aminostransferase, aspartate aminotransferase (AST), amylase and bilirubin levels were assessed. Pancreatic tissues were evaluated under light microscopy for the presence of edema, acinar necrosis, hemorrhage, inflammation and perivascular infiltration. Results: Amylase, serum AST, edema and inflammatory infiltration levels differed between groups (amylase: p = 0.0001, serum AST: p = 0.001, edema: p = 0.0001 and inflammatory infiltration: p = 0.002), group 1 showing the highest amylase, serum AST and edema levels. The lowest levels of edema were found in group 3. Conclusion: In an experimental pancreatitis model in rats, MMF proved to exert a beneficial effect on biochemical and histopathological parameters.

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Kinetic study of TNF‐α production and its regulatory mechanisms in acinar cells during acute pancreatitis induced by bile–pancreatic duct obstruction

Cited by 56 publications

References 43 publications

Expression of Nitric Oxide Synthase Isoforms and Nitric Oxide Production in Acute Pancreatitis and Associated Lung Injury

Expression of Nitric Oxide Synthase Isoforms and Nitric Oxide Production in Acute Pancreatitis and Associated Lung Injury

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

Effect of Mycophenolate Mofetil on Cerulein-Induced Acute Pancreatitis

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