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

Seleznik, GM, Reding, T, Peter, L, Gupta, A, Steiner, SG, Sonda, S ORCID: 0000-0001-8152-3425, Verbeke, CS, Dejardin, E, Khatkov, I, Segerer, S, Heikenwalder, M and Graf, R 2017 , 'Development of autoimmune pancreatitis is independent of CDKN1A/p21-mediated pancreatic inflammation' , Gut: An International Journal of Gastroenterology and Hepatology, vol. 67, no. 9 , pp. 1663-1673 , doi: 10.1136/gutjnl-2016-313458.

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Abstract

Objective: Chronic pancreatitis (CP) and autoimmunepancreatitis (AIP) are characterised by differentinflammatory processes. If pancreatic inflammation isa prerequisite for autoimmunity is still unclear. AIP isconsidered mostly a T cell-mediated disease; however, ininduction of CP, macrophages play a pivotal role. p21—amember of cyclin-dependent kinase inhibitors—caninfluence inflammatory processes, in particular canregulate T cell activation and promote macrophagedevelopment. We therefore examined the role of p21-mediated inflammation in AIP.Design: We intercrossed lymphotoxin (LT)overexpressing mice (Tg(Ela1-LTa,b))—a model to studyAIP development—with p21-deficient mice. Furthermore,we characterised p21 expression in human AIP and nonAIPspecimens.Results: p21 deficiency in LT mice (LTp21−/−) preventedearly pancreatic injury and reduced inflammation. Inacinar cells, diminished proliferation and abrogatedactivation of non-canonical nuclear factor kappa-lightchain-enhancerof activated B cell (NF-κB) pathwaywas observed. In contrast, 12-month-old LT mice withand without p21 had similar inflammatory signaturesand T–B cell infiltration. Interestingly, LT and LTp21−/−mice had comparable tertiary lymphoid organs (TLOs),autoantibodies and elevated IgG levels. However, acinarcell proliferation, acinar-to-ductal metaplasia and acinarnon-canonical NF-κB pathway activation remainedimpaired in LTp21−/− pancreata.Conclusions: Our findings indicate that p21 is crucialfor pancreatic inflammation in LT-driven pancreatic injury.p21 is involved in early acinar secretion of inflammatorymediators that attract innate immune cells. However, p21is not essential for humoral immune response, accountablefor autoimmunity. Remarkably, p21 renders acinar cellsless susceptible to proliferation and transdifferentiation. Wetherefore suggest that AIP can also develop independent ofchronic inflammatory processes.

Item Type: Article
Authors/Creators:Seleznik, GM and Reding, T and Peter, L and Gupta, A and Steiner, SG and Sonda, S and Verbeke, CS and Dejardin, E and Khatkov, I and Segerer, S and Heikenwalder, M and Graf, R
Keywords: Autoimmune pancreatitis, p21, inflammation
Journal or Publication Title: Gut: An International Journal of Gastroenterology and Hepatology
Publisher: B M J Publishing Group
ISSN: 0017-5749
DOI / ID Number: 10.1136/gutjnl-2016-313458
Copyright Information:

Copyright 2018 the authors

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