Pancreatic acinar cell
necrosis and inflammatory responses are two key
pathologic processes in
acute pancreatitis (AP), which determines the severity and outcome of the disease. Recent studies suggest that necroptosis, a programed form of
necrosis, is involved in the pathogenesis of AP, but the underlying mechanisms remain unknown. We investigated the expression of necrosome components, including
receptor-interacting protein (RIP) 1, RIP3, and mixed lineage
kinase domain-like (MLKL), and the molecular mechanisms in
pancreatitis-associated necroptosis. We found that RIP3 and phosphorylated MLKL expression was positively related to the degree of
necrosis, whereas RIP1 expression was negatively related to the degree of
necrosis. Pharmacologic inhibition of RIP1
kinase activity exerted no protection against
caerulein/
cholecystokinin-8-induced AP, but knockdown of RIP1 with
siRNA increased acinar cell
necrosis and inhibition of NF-κB activation. RIP1 inhibition led to enhanced RIP3 expression. RIP3 and MLKL inhibition decreased acinar cell
necrosis, in which the inhibition of RIP3 reduced the phosphorylation level of MLKL. RIP3 inhibition had no effect on
trypsinogen activation but partly inhibited
inflammasome activation. Our study strongly suggests that the imbalance between RIP1 and RIP3 shifts the cell death to
necrosis, which unravels a new molecular pathogenesis of mechanism of AP and may provide insight into the development of novel therapeutic agent for other
necrosis-related diseases.