A pan caspase inhibitor decreases caspase-1, IL-1αand IL-1β, and protects against necrosis of cisplatin-treated freshly isolated proximal tubules

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Abstract

Caspase-1, IL-1α, and IL-1β are known to be activated in the NLRP3 inflammasome. The inflammasome is activated mostly in inflammatory cells. The presence of inflammasome proteins in proximal tubules (PTs) and the effect of cisplatin-treatment or caspase inhibition on inflammasome proteins in PTs are not known. The aim of this study was to investigate the effect of cisplatin on inflammasome proteins in freshly isolated PTs and also to determine the effect of caspase inhibition on inflammasome proteins and PT injury. PTs were isolated using collagenase digestion and Percoll centrifugation. After recovery period, freshly isolated PTs were incubated with vehicle, 50 µM cisplatin or 50 µM cisplatin plus 50 µM pan caspase inhibitor, QVD-OPH. PTs treated with 50 µM cisplatin showed Propidium Iodide staining indicative of necrosis. Necrotic cells (%) were 2.2 in Vehicle-treated, 37.7 in Cisplatin-treated (p < 0.05 vs. Vehicle), and 3.3 in QVD-treated (p < 0.05 vs. Cisplatin). LDH release (%), a marker of cell membrane damage seen in necrosis was 7.1 in Vehicle-treated, 39.7 in Cisplatin-treated (p < 0.05 vs. Vehicle), and 13.5 in QVD-treated (p < 0.05 vs. Cisplatin). Caspase-1 activity and active caspase-1 protein (10 kDa) were significantly increased in Cisplatin-treated PTs. NLRP3 was strongly expressed in PTs, but there were no significant changes between groups. Pro-apoptotic BID (22 kDa) was unchanged between groups. IL-1α and IL-1β activity was increased in Cisplatin-treated PTs. QVD-OPH co-treatment decreased caspase-1, IL-1α, and IL-1β. In summary, caspase inhibition decreases caspase-1, IL-1α, and IL-1β but not NLRP3 or BID protein and protects against necrosis in cisplatin-treated freshly isolated PTs.

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Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009.

G Kroemer, L Galluzzi, P Vandenabeele … (2009)

Different types of cell death are often defined by morphological criteria, without a clear reference to precise biochemical mechanisms. The Nomenclature Committee on Cell Death (NCCD) proposes unified criteria for the definition of cell death and of its different morphologies, while formulating several caveats against the misuse of words and concepts that slow down progress in the area of cell death research. Authors, reviewers and editors of scientific periodicals are invited to abandon expressions like 'percentage apoptosis' and to replace them with more accurate descriptions of the biochemical and cellular parameters that are actually measured. Moreover, at the present stage, it should be accepted that caspase-independent mechanisms can cooperate with (or substitute for) caspases in the execution of lethal signaling pathways and that 'autophagic cell death' is a type of cell death occurring together with (but not necessarily by) autophagic vacuolization. This study details the 2009 recommendations of the NCCD on the use of cell death-related terminology including 'entosis', 'mitotic catastrophe', 'necrosis', 'necroptosis' and 'pyroptosis'.

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The NLRP3 inflammasome: a sensor for metabolic danger?

Kate Schroder, Rongbin Zhou, Jurg Tschopp (2010)

Interleukin-1beta (IL-1beta), reactive oxygen species (ROS), and thioredoxin-interacting protein (TXNIP) are all implicated in the pathogenesis of type 2 diabetes mellitus (T2DM). Here we review mechanisms directing IL-1beta production and its pathogenic role in islet dysfunction during chronic hyperglycemia. In doing so, we integrate previously disparate disease-driving mechanisms for IL-1beta, ROS, and TXNIP in T2DM into one unifying model in which the NLRP3 inflammasome plays a central role. The NLRP3 inflammasome also drives IL-1beta maturation and secretion in another disease of metabolic dysregulation, gout. Thus, we propose that the NLRP3 inflammasome contributes to the pathogenesis of T2DM and gout by functioning as a sensor for metabolic stress.