Protective Effects of Necrostatin-1 in Acute Pancreatitis: Partial Involvement of Receptor Interacting Protein Kinase 1.

Ouyang, Yulin; Wen, Li; Armstrong, Jane A.; Chvanov, Michael; Latawiec, Diane; Cai, Wenhao; Awais, Mohammad; Mukherjee, Rajarshi; Huang, Wei; Gough, Peter J.; Bertin, John; Tepikin, Alexei V.; Sutton, Robert; Criddle, David N.; Bultynck, Geert; Tikkanen, Ritva

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.

PROTEIN kinases; RECEPTOR-interacting proteins; INDOLEAMINE 2,3-dioxygenase; PANCREATIC acinar cells; PROTEIN receptors; PROGRAMMED cell death 1 receptors

Cells (2073-4409), 2021, Vol 10, Issue 5, p1035

2073-4409

Academic Journal

10.3390/cells10051035