title: Cell death in pancreatitis: caspases protect from necrotizing pancreatitis.
abstract: Mechanisms of cell death in pancreatitis remain unknown. Parenchymal necrosis is a major complication of pancreatitis; also, the severity of experimental pancreatitis correlates directly with necrosis and inversely with apoptosis. Thus, shifting death responses from necrosis to apoptosis may have a therapeutic value. To determine cell death pathways in pancreatitis and the possibility of necrosis/apoptosis switch, we utilized the differences between the rat model of cerulein pancreatitis, with relatively high apoptosis and low necrosis, and the mouse model, with little apoptosis and high necrosis. We found that caspases were greatly activated during cerulein pancreatitis in the rat but not mouse. Endogenous caspase inhibitor X-linked inhibitor of apoptosis protein (XIAP) underwent complete degradation in the rat but remained intact in the mouse model. Furthermore, XIAP inhibition with embelin triggered caspase activation in the mouse model, implicating XIAP in caspase blockade in pancreatitis. Caspase inhibitors decreased apoptosis and markedly stimulated necrosis in the rat model, worsening pancreatitis parameters. Conversely, caspase induction with embelin stimulated apoptosis and decreased necrosis in mouse model. Thus, caspases not only mediate apoptosis but also protect from necrosis in pancreatitis. One protective mechanism is through degradation of receptor-interacting protein (RIP), a key mediator of "programmed" necrosis. We found that RIP was cleaved (i.e. inactivated) in the rat but not the mouse model. Caspase inhibition restored RIP levels; conversely, caspase induction with embelin triggered RIP cleavage. Our results indicate key roles for caspases, XIAP, and RIP in the regulation of cell death in pancreatitis. Manipulating these signals to change the pattern of death responses presents a therapeutic strategy for treatment of pancreatitis.
authors.affiliation: Veterans Affairs Greater Los Angeles Healthcare System and Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90073, USA.
authors.forename: Olga A
authors.initials: OA
authors.lastname: Mareninova
authors.forename: Kai-Feng
authors.initials: KF
authors.lastname: Sung
authors.forename: Peggy
authors.initials: P
authors.lastname: Hong
authors.forename: Aurelia
authors.initials: A
authors.lastname: Lugea
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Pandol
authors.forename: Ilya
authors.initials: I
authors.lastname: Gukovsky
authors.forename: Anna S
authors.initials: AS
authors.lastname: Gukovskaya
mesh_terms: D000681:Amylases / Q000097:blood; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3; D053179:Caspase 7; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death; D002462:Cell Membrane / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007249:Inflammation; D008049:Lipase / Q000097:blood / Q000378:metabolism; D008297:Male; D051379:Mice; D009336:Necrosis; D010179:Pancreas / Q000378:metabolism; D010195:Pancreatitis / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D015398:Signal Transduction; D013045:Species Specificity; D013997:Time Factors; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; D017346:Protein Serine-Threonine Kinases; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse; D008049:Lipase; D000681:Amylases; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; C505524:Casp7 protein, mouse; C506434:Casp9 protein, mouse; C506435:Casp9 protein, rat; D053148:Caspase 3; D053179:Caspase 7; D053453:Caspase 9; D020169:Caspases