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, Development of autoimmune pancreatitis is independent of CDKN1A/p21-mediated pancreatic inflammation, Gut: An International Journal of Gastroenterology and Hepatology, 67, (9) pp. 1663-1673. ISSN 0017-5749 (2017) [Refereed Article]
Copyright 2018 the authors
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 nonAIP 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-lightchain-enhancer of activated B cell (NF-κB) 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-κB 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.
|Item Type:||Refereed Article|
|Keywords:||Autoimmune pancreatitis, p21, inflammation|
|Research Division:||Biological Sciences|
|Research Group:||Biochemistry and cell biology|
|Research Field:||Signal transduction|
|Objective Group:||Clinical health|
|Objective Field:||Clinical health not elsewhere classified|
|UTAS Author:||Sonda, S (Dr Sabrina Sonda)|
|Web of Science® Times Cited:||4|
|Deposited By:||Health Sciences|
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