Pancreas-specific RelA/p65 truncation increases susceptibility of acini to inflammation-associated cell death following cerulein pancreatitis

Algül, Hana; Treiber, Matthias; Lesina, Marina; Nakhai, Hassan; Saur, Dieter; Geisler, Fabian; Pfeifer, Alexander; Paxian, Stephan; Schmid, Roland M.

doi:10.1172/jci29882

Cited by 167 publications

(145 citation statements)

References 70 publications

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“…The experimentally induced reduction in the expression of pancreatic RegIIIβ is followed by an exacerbation of pancreatitis (29,30). The expression of RegIIIβ is up-regulated in acinar cells during the acute phase of pancreatitis and paralleled the severity of pancreatitis (21,28). However, this is not the case in PACAP-Tg mice; while the cerulein-induced pancreatitis is aggravated at 12 h, the expression of RegIIIβ at 24 h was significantly lower than that of wild-type mice (Fig.…”

Section: Discussionmentioning

confidence: 89%

Over-Expression of Pancreatic Pituitary Adenylate Cyclase–Activating Polypeptide (PACAP) Aggravates Cerulein-Induced Acute Pancreatitis in Mice

Hamagami¹,

Sakurai²,

Shintani³

et al. 2009

J Pharmacol Sci

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Abstract. Development of human chronic pancreatitis is associated with intrapancreatic accumulation of pituitary adenylate cyclase-activating polypeptide (PACAP) accompanied with an altered inflammatory response (Michalski et al., Am J Physiol Gastrointest Liver Physiol. 2008;294:G50-G57). To investigate the role of pancreatic PACAP in the development of acute pancreatitis, we employed transgenic mice over-expressing PACAP in pancreatic β-cells (PACAP-Tg). In comparison to wild-type mice, PACAP-Tg mice exhibited more severe pathophysiological signs of the cerulein-induced pancreatitis at 12 h, as evidenced by higher serum amylase and lipase levels accompanied by the exacerbation of pancreatic edema, necrosis, and inflammation. Cerulein treatment increased mRNA expression of several proinflammatory cytokines (TNFα, IL-1β, and IL-6) at 12 h with similar magnitude both in wild-type and PACAPTg mice. In addition, the mRNA and protein levels of regenerating gene III β (RegIIIβ), a key factor in the pancreatic response to acute pancreatitis, were up-regulated at 24 h in wild-type mice upon cerulein administration, whereas they were attenuated in PACAP-Tg mice. These data indicate that over-expressed PACAP in pancreas enhances the cerulein-induced inflammatory response of both acinar cells, leading to aggravated acute pancreatitis, which was accompanied by a down-regulation of RegIIIβ, an anti-inflammatory factor.

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Section: Discussionmentioning

confidence: 89%

Over-Expression of Pancreatic Pituitary Adenylate Cyclase–Activating Polypeptide (PACAP) Aggravates Cerulein-Induced Acute Pancreatitis in Mice

Hamagami¹,

Sakurai²,

Shintani³

et al. 2009

J Pharmacol Sci

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“…Mice that were Stat3 LoxP/LoxP (18) or Rela LoxP/LoxP (19) were crossed with Alb-Cre tg/tg mice expressing Cre-recombinase from an albumin promoter (20) Microarray. Microarrays were performed on total liver RNA as described in figure legends.…”

Section: Additional Information Is In Supplemental Methodsmentioning

confidence: 99%

Hepatocyte-specific mutation of both NF-κB RelA and STAT3 abrogates the acute phase response in mice

Quinton

Blahna²,

Jones³

et al. 2012

J. Clin. Invest.

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The acute phase response is an evolutionarily conserved reaction in which physiological stress triggers the liver to remodel the blood proteome. Although thought to be involved in immune defense, the net biological effect of the acute phase response remains unknown. As the acute phase response is stimulated by diverse cytokines that activate either NF-κB or STAT3, we hypothesized that it could be eliminated by hepatocyte-specific interruption of both transcription factors. Here, we report that the elimination in mice of both NF-κB p65 (RelA) and STAT3, but neither alone, abrogated all acute phase responses measured. The failure to respond was consistent across multiple different infectious, inflammatory, and noxious stimuli, including pneumococcal pneumonia. When the effects of infection were analyzed in detail, pneumococcal pneumonia was found to alter the expression of over a thousand transcripts in the liver. This outcome was inhibited by the combined loss of RelA and STAT3. Moreover, this interruption of the acute phase response increased mortality and exacerbated bacterial dissemination during pneumonia, possibly as a result of acute humoral enhancement of macrophage opsonophagocytosis, which was impaired in the mutant mice. Thus, we conclude that RelA and STAT3 are essential for stress-induced transcriptional remodeling in the liver and the subsequent activation of the acute phase response, whose functional role includes compartmentalization of local infection.

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“…Serum PSP was transiently increased after stress such as anesthesia in animals without pancreatic injury (82) and critical diseased in the ICU patients (77). Pro-and anti-inflammatory cytokines might induce expression of PSP/Reg/PAP family (11, 29,71,72,83). Pancreatic stellate cells (PSC) play a central role in fibrogenesis associated with acute and chronic pancreatitis.…”

Section: Anti-inflammatory Activity and Prognostic Indicatormentioning

confidence: 99%

Pancreatic Stone Protein/Regenerating Protein Family in Pancreatic and Gastrointestinal Diseases

Jin

Hayakawa

et al. 2011

Intern. Med.

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Pancreatic stone protein (PSP; reported in 1979), pancreatitis-associated protein (PAP; 1984) and regenerating protein (Reg I;1988) were discovered independently in the fields of the exocrine (pancreatitis) and endocrine (diabetes) pancreas. Subsequent analysis revealed that PSP and Reg I are identical and PAP belongs to the same protein family. PSP/Reg I and PAP share a selective and specific trypsin cleavage site and result in insoluble fibrils (PTP, PATP). Search for a functional role of PSP had led to the idea that it might serve as an inhibitor in pancreatic stone formation and PSP was renamed lithostathine. Inhibitory effects of lithostathine in stone formation have been questioned. Evidence so far obtained can support a lithogenic role rather than a lithostatic role of PSP. PAP and its isoforms have been investigated mainly regarding responses to inflammation and stress. Reg I and its isoforms have been examined on regeneration, growth and mitogenesis in gastrointestinal neoplastic diseases as well as diabetes. Evidence obtained can be applied in the prediction of prognosis and therapy for inflammatory and neoplastic diseases.

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Pancreas-specific RelA/p65 truncation increases susceptibility of acini to inflammation-associated cell death following cerulein pancreatitis

Cited by 167 publications

References 70 publications

Over-Expression of Pancreatic Pituitary Adenylate Cyclase–Activating Polypeptide (PACAP) Aggravates Cerulein-Induced Acute Pancreatitis in Mice

Over-Expression of Pancreatic Pituitary Adenylate Cyclase–Activating Polypeptide (PACAP) Aggravates Cerulein-Induced Acute Pancreatitis in Mice

Hepatocyte-specific mutation of both NF-κB RelA and STAT3 abrogates the acute phase response in mice

Pancreatic Stone Protein/Regenerating Protein Family in Pancreatic and Gastrointestinal Diseases

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