Loss of p21WAF1/Cip1 accelerates senescence and acinar-to-ductal metaplasia formation during pancreatitis

Grabliauskaite, Kamilé; Sonda, Sabrina; Saponara, Enrica; Graf, Theresia Reding; Graf, Rolf

doi:10.1016/j.pan.2014.05.717

Cited by 7 publications

(10 citation statements)

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“…In contrast to our current findings, p21 −/− mice were reported to have enhanced ADM development in a model of cerulein-induced pancreatitis 23. The induction of pancreatitis is fundamentally different in the two models.…”

Section: Discussioncontrasting

confidence: 99%

“…Obviously, none of the current mouse models available reflect the human disease fully; yet, both studies revealed important aspects on the role of p21 in the development of pancreatitis. Grabliauskaite et al 23 showed that lack of p21 increased DNA damage and cellular senescence in acinar cells, whereas our study suggests an important role of p21 in the LT-mediated induction of non-canonical NF-κB signalling.…”

Section: Discussioncontrasting

confidence: 81%

“…However, we show that at the age of 12 months, inflammatory cells are able to infiltrate and proliferate in the pancreas and produce inflammatory mediators, without inducing acinar cell proliferation. Furthermore, we have previously shown23 that during cerulein-induced acute pancreatitis, inflammation was comparable between p21 −/− and p21 +/+ groups, suggesting that inflammatory cells are not affected by the loss of p21. Therefore, our data, and previously published reports,37 imply the opposite sequence, that is, acinar cells produce cytokines and chemokines, which then drive the inflammatory cell accumulation.…”

Section: Discussionmentioning

confidence: 80%

“…We have recently demonstrated a gate-keeper role of p21 in acute pancreatitis, where p21 limits activation of senescence and ADM formation during regeneration 23. To understand the role of p21 in pancreatic inflammation and autoimmunity, we generated a mouse model by breeding a well-characterised model of AIP (Tg(Ela1-LTa,b))24 with p21-deficient mice.…”

Section: Introductionmentioning

confidence: 99%

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Development of autoimmune pancreatitis is independent of CDKN1A/p21-mediated pancreatic inflammation

Seleznik

Reding

Peter

et al. 2017

Gut

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Our findings indicate that p21 is crucial for pancreatic inflammation in LT-driven pancreatic injury. p21 is involved in early acinar secretion of inflammatory mediators that attract innate immune cells. However, p21 is not essential for humoral immune response, accountable for autoimmunity. Remarkably, p21 renders acinar cells less susceptible to proliferation and transdifferentiation. We therefore suggest that AIP can also develop independent of chronic inflammatory processes.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussioncontrasting

confidence: 81%

Section: Discussionmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Development of autoimmune pancreatitis is independent of CDKN1A/p21-mediated pancreatic inflammation

Seleznik

Reding

Peter

et al. 2017

Gut

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“…In support of this hypothesis, DNA damage in acinar cells, known to be triggered by inflammation (reviewed in Kidane et al, 2014), was lower in both MS-275-treated C57BL/6 and p21 À/À mice, as shown by the quantification of γH2AX ( Figure 6A), an early hallmark of active DNA damage. Acinar DNA damage (Grabliauskaite et al, 2015a) and macrophage infiltration (Liou et al, 2013) are also associated with the development of ADM, a transient de-differentiation of acinar cells occurring during the regenerative phase of pancreatitis. MS-275 reduced ADM formation 72 h after induction of pancreatitis ( Figure 6B).…”

Section: Inhibition Of Class I Hdac Reduces Pancreatic Tissue Damage mentioning

confidence: 99%

Class I histone deacetylase inhibition improves pancreatitis outcome by limiting leukocyte recruitment and acinar‐to‐ductal metaplasia

Bombardo

Saponara

Malagola

et al. 2017

British J Pharmacology

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BACKGROUND AND PURPOSEPancreatitis is a common inflammation of the pancreas with rising incidence in many countries. Despite improvements in diagnostic techniques, the disease is associated with high risk of severe morbidity and mortality and there is an urgent need for new therapeutic interventions. In this study, we evaluated whether histone deacetylases (HDACs), key epigenetic regulators of gene transcription, are involved in the development of the disease. EXPERIMENTAL APPROACHWe analysed HDAC regulation during cerulein-induced acute, chronic and autoimmune pancreatitis using different transgenic mouse models. The functional relevance of class I HDACs was tested with the selective inhibitor MS-275 in vivo upon pancreatitis induction and in vitro in activated macrophages and primary acinar cell explants. KEY RESULTSHDAC expression and activity were up-regulated in a time-dependent manner following induction of pancreatitis, with the highest abundance observed for class I HDACs. Class I HDAC inhibition did not prevent the initial acinar cell damage. However, it effectively reduced the infiltration of inflammatory cells, including macrophages and T cells, in both acute and chronic phases of the disease, and directly disrupted macrophage activation. In addition, MS-275 treatment reduced DNA damage in acinar cells and limited acinar de-differentiation into acinar-to-ductal metaplasia in a cell-autonomous manner by impeding the EGF receptor signalling axis. CONCLUSIONS AND IMPLICATIONSThese results demonstrate that class I HDACs are critically involved in the development of acute and chronic forms of pancreatitis and suggest that blockade of class I HDAC isoforms is a promising target to improve the outcome of the disease. IntroductionAbnormal activity of histone deacetylases (HDACs), a family of enzymes involved in the epigenetic control of gene transcription, has been implicated in the aetiology and development of several malignancies. However, recent evidence indicates that HDACs are also involved in the development of inflammatory diseases, highlighting the potential of targeting the activity of HDACs as a therapeutic approach to improve the outcome of rheumatoid arthritis (Choo et al., 2010(Choo et al., , 2013, neuritis (Zhang et al., 2010;Zhang and Schluesener, 2013), cholitis (Felice et al., 2015) and autoimmunity (Hancock et al., 2012).HDACs control the acetylation status of histone and non-histone proteins, thus regulating the expression of target genes (reviewed in Delcuve et al., 2012). The complexity of acetylation-based epigenetic regulation is reflected by the size of the mammalian HDAC family, composed of 11 zinc-dependent enzymes divided into three subfamilies (classes I, II and IV) and seven NAD-dependent enzymes in a fourth (sirtuin) subfamily (class III), with non-redundant functions.The function of HDAC subfamilies in the pathophysiology of pancreatitis, a highly debilitating inflammatory disease with a potentially lethal outcome, has not been thoroughly investigated. During pancreatitis, the ...

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Baicalein inhibits acinar‐to‐ductal metaplasia of pancreatic acinal cell AR42J via improving the inflammatory microenvironment

Luo

Bai

et al. 2018

Journal Cellular Physiology

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers. Recent research has demonstrated that chronic pancreatitis (CP) is associated with an increased risk of PDAC, partly due to acinar-to-ductal metaplasia (ADM). Baicalein has been shown to exert anti-inflammatory and anti-tumor effects for CP or PDAC, respectively. The aim of our study was to investigate the effect of baicalein, and the putative underlying mechanism, on inflammatory cytokines-induced ADM of rat pancreatic acinar cell line AR42J. To investigate ADM and baicalein effects in vitro, AR42J were treated with recombinant rat Tumor Necrosis Factor alpha (rTNFα) with or without baicalein for 5 days. Results showed that rTNFα-induced AR42J cells switched their phenotype from dominantly amylase-positive acinar cells to dominantly cytokeratin 19-positive ductal cells. Moreover, expression of the transcripts for TNFα or Hes-1, a Notch target, was up-regulated in these cells. Interestingly, baicalein reduced the population of ADM as well as cytokines gene expression but not Hes-1. Baicalein inhibited NF-κB activation induced by rTNFα in AR42J, but no effect on Notch 1activation. Moreover, baicalein suppressed the secretion of TNFα and Nitric Oxide (NO) in macrophages stimulated with LPS and further inhibited ADM of conditional medium-treated AR42J cells. Baicalein also suppressed the inflammatory response of LPS-activated macrophages, thereby inhibited ADM of AR42J by altering their microenvironment. Taken together, our study indicates that baicalein reduces rTNFα-induced ADM of AR42J cells by inhibiting NF-κB activation. It also sheds new light on Chinese material medica therapy of pancreatitis and thereby prevention of PDAC.

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Loss of p21WAF1/Cip1 accelerates senescence and acinar-to-ductal metaplasia formation during pancreatitis

Cited by 7 publications

References 0 publications

Development of autoimmune pancreatitis is independent of CDKN1A/p21-mediated pancreatic inflammation

Development of autoimmune pancreatitis is independent of CDKN1A/p21-mediated pancreatic inflammation

Class I histone deacetylase inhibition improves pancreatitis outcome by limiting leukocyte recruitment and acinar‐to‐ductal metaplasia

Baicalein inhibits acinar‐to‐ductal metaplasia of pancreatic acinal cell AR42J via improving the inflammatory microenvironment

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