NF-κB activation in pancreas induces pancreatic and systemic inflammatory response

Chen, Xueqing; Ji, Baoan; Han, Bing; Ernst, Stephen A.; Simeone, Diane M.; Logsdon, Craig D.

doi:10.1053/gast.2002.31060

Cited by 202 publications

(156 citation statements)

References 33 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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“…16 Conversely, intraductally administered in vivo gene transfer of RelA led to NFkB activation, acinar damage and acute pancreatitis in rats. 17 Thus, it remains unclear whether NFkB activation in pancreas is protective or deleterious. 18 Remarkably, in the acini of CP with severe fibrosis, we found a 69-fold NFkB2 mRNA expression, eventually tilting the balance in favor of apoptotic cell death in the exocrine compartment.…”

Section: Discussionmentioning

confidence: 99%

Parenchymal regression in chronic pancreatitis spares islets reprogrammed for the expression of NFκB and IAPs

Hasel

Bhanot

Heydrich

et al. 2005

Laboratory Investigation

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In advanced chronic pancreatitis (CP), islets are preserved even in the midst of scarring. We recently showed in CP local production of interferon (IFN)c, transforming growth factor (TGF)b and death receptor ligand TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), along with functional death receptor neoexpression and apoptosis in exocrine but not in endocrine cells. However, islets are strongly induced for TRAILreceptor(R)-4 lacking the functional death domain. TRAIL-R4 signaling in T cells induces NFjB, which activates antiapoptotic programs. Here, we demonstrate that in insulinoma cells CM, TGFb/IFNc/TRAIL in combination induced TRAIL-R4 surface expression. TRAIL/IFNc upregulated NFjB subunits and its target gene survivin while downmodulating IjBa mRNA. RelA transcriptional activity increased upon stimulation with IFNc and IFNc/ TRAIL. In situ, normal pancreatic epithelia had low mRNA levels of NFjB subunits. These were higher in parenchymal areas of CP with severe fibrosis and highest in islets. NFjB-regulated proteins IjBa, survivin and another apoptosis inhibitor, cIAP1, were found in corresponding sites, again at highest levels in islets surrounded by fibrosis. In conclusion, islets in CP not only evade immune attack by nonexposure of functional death receptors in the presence of TRAIL-R4 but also additionally neoexpress NFjB and its target genes, survivin and cIAP1, to protect themselves from apoptosis.

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“…In the second phase, there is intrapancreatic inflammation through a variety of mechanisms and pathways (16,(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). In the third phase, there is extrapancreatic inflammation including acute respiratory syndrome (ARDS) (16,(19)(20)(21)29).…”

Section: Pathophysiologymentioning

confidence: 99%

Practice Guidelines in Acute Pancreatitis

Banks

Freeman

2006

Am J Gastroenterology

1,622

955

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NF-κB activation in pancreas induces pancreatic and systemic inflammatory response

Cited by 202 publications

References 33 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

Parenchymal regression in chronic pancreatitis spares islets reprogrammed for the expression of NFκB and IAPs

Practice Guidelines in Acute Pancreatitis

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