Ouyang, Yulin, Wen, Li, Armstrong, Jane A, Chvanov, Michael, Latawiec, Diane 
ORCID: 0000-0003-3097-9064, Cai, Wenhao, Awais, Mohammad, Mukherjee, Rajarshi ORCID: 0000-0003-0982-7883, 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-.
ISSN 2073-4409, 2073-4409
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Text
cells-1156529 final.pdf - Author Accepted Manuscript Download (730kB) | Preview |
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 (RIPK1K45A: 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 RIPK1K45A 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 RIPK1K45A mice. Inhibition of IDO with EPA was protective in TLCS‐AP. Both Nec‐1 and RIPK1K45A modification inhibited TLCS‐ and FAEE‐induced PAC necrosis in vitro. Nec‐1 did not affect TLCS‐induced Ca2+ 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 & Life Sciences Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology > Inst. Systems, Molec & Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 10 May 2021 10:03 |
| Last Modified: | 16 Jun 2026 09:25 |
| DOI: | 10.3390/cells10051035 |
| Related Websites: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3121736 |
| Disclaimer: | The University of Liverpool is not responsible for content contained on other websites from links within repository metadata. Please contact us if you notice anything that appears incorrect or inappropriate. |
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