Ouyang, Yulin, Wen, Li, Armstrong, Jane A, Chvanov, Michael, Latawiec, Diane, Cai, Wenhao 
ORCID: 0000-0002-4328-3341, Awais, Mohammad, Mukherjee, Rajarshi, Huang, Wei, Gough, Peter J et al (show 4 more authors)
(2021)
Protective Effects of Necrostatin-1 in Acute Pancreatitis: Partial Involvement of Receptor Interacting Protein Kinase 1.
CELLS, 10 (5).
1035-.
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Abstract
Acute pancreatitis (AP) is a severe and potentially fatal disease caused predominantly by alcohol excess and gallstones, which lacks a specific therapy. The role of Receptor-Interacting Protein Kinase 1 (RIPK1), a key component of programmed necrosis (Necroptosis), is unclear in AP. We assessed the effects of RIPK1 inhibitor Necrostatin-1 (Nec-1) and RIPK1 modification (RIPK1<sup>K45A</sup>: kinase dead) in bile acid (TLCS-AP), alcoholic (FAEE-AP) and caerulein hyperstimulation (CER-AP) mouse models. Involvement of collateral Nec-1 target indoleamine 2,3-dioxygenase (IDO) was probed with the inhibitor Epacadostat (EPA). Effects of Nec-1 and RIPK1<sup>K45A</sup> were also compared on pancreatic acinar cell (PAC) fate in vitro and underlying mechanisms explored. Nec-1 markedly ameliorated histological and biochemical changes in all models. However, these were only partially reduced or unchanged in RIPK1<sup>K45A</sup> mice. Inhibition of IDO with EPA was protective in TLCS-AP. Both Nec-1 and RIPK1<sup>K45A</sup> modification inhibited TLCS- and FAEE-induced PAC necrosis in vitro. Nec-1 did not affect TLCS-induced Ca<sup>2+</sup> entry in PACs, however, it inhibited an associated ROS elevation. The results demonstrate protective actions of Nec-1 in multiple models. However, RIPK1-dependent necroptosis only partially contributed to beneficial effects, and actions on targets such as IDO are likely to be important.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | acute pancreatitis, receptor-interacting protein kinase 1, RIPK1, necrostatin-1, necroptosis, cell death, indoleamine 2, 3-dioxygenase, epacadostat |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 10 May 2021 10:03 |
| Last Modified: | 23 Mar 2023 10:59 |
| DOI: | 10.3390/cells10051035 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3121736 |
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