Article (Scientific journals)
Development of autoimmune pancreatitis is independent of CDKN1A/p21-mediated pancreatic inflammation.
Seleznik, Gitta M.; Reding, Theresia; Peter, Lukas et al.
2018In Gut
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Keywords :
autoimmunity; cell cycle; experimental pancreatitis; inflammation
Abstract :
[en] OBJECTIVE: Chronic pancreatitis (CP) and autoimmune pancreatitis (AIP) are characterised by different inflammatory processes. If pancreatic inflammation is a prerequisite for autoimmunity is still unclear. AIP is considered mostly a T cell-mediated disease; however, in induction of CP, macrophages play a pivotal role. p21-a member of cyclin-dependent kinase inhibitors-can influence inflammatory processes, in particular can regulate T cell activation and promote macrophage development. 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 study AIP development-with p21-deficient mice. Furthermore, we characterised p21 expression in human AIP and non-AIP specimens. RESULTS: p21 deficiency in LT mice (LTp21(-/-)) prevented early pancreatic injury and reduced inflammation. In acinar cells, diminished proliferation and abrogated activation of non-canonical nuclear factor kappa-light-chain-enhancer of activated B cell (NF-kappaB) pathway was observed. In contrast, 12-month-old LT mice with and without p21 had similar inflammatory signatures and T-B cell infiltration. Interestingly, LT and LTp21(-/-) mice had comparable tertiary lymphoid organs (TLOs), autoantibodies and elevated IgG levels. However, acinar cell proliferation, acinar-to-ductal metaplasia and acinar non-canonical NF-kappaB pathway activation remained impaired in LTp21(-/-) pancreata. CONCLUSIONS: 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Seleznik, Gitta M.
Reding, Theresia
Peter, Lukas
Gupta, Anurag
Steiner, Sabrina G.
Sonda, Sabrina
Verbeke, Caroline S.
Dejardin, Emmanuel ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : Labo of Molecular Immunol. and Signal Transduction
Khatkov, Igor
Segerer, Stephan
Heikenwalder, Mathias
Graf, Rolf
Language :
English
Title :
Development of autoimmune pancreatitis is independent of CDKN1A/p21-mediated pancreatic inflammation.
Publication date :
2018
Journal title :
Gut
ISSN :
0017-5749
eISSN :
1468-3288
Publisher :
BMJ Publishing Group, United Kingdom
Peer reviewed :
Peer Reviewed verified by ORBi
Commentary :
(c) Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
Available on ORBi :
since 15 January 2018

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