SERINE PROTEASE-LIKE ACTIVITY, BUT NOT CALCIUM-INDEPENDENT PHOSPHOLIPASE A2

Washington University, Saint Louis MO

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Two intracellular NLR family members, Nlc4 and Nlrp3, play a critical role in the activation of caspase-1 and release of mature IL-1b in response to specific microbial stimuli. Based on the use of chemical inhibitors, several studies have suggested an involvement of calcium-independent phospholipase A2 (iPLA2) in inflammasome activation and IL-1b secretion. Here we use pharmacological and genetic approaches to study the role of iPLA2 in the activation of caspase-1 induced through the Nlrc4 and Nlrp3 inflammasomes. Bromoenol lactone (BEL), an inhibitor that was originally used to support a role for iPLA2 in inflammasome activation, prevented caspase-1 processing induced not only by LPS and ATP, but also by Salmonella infection and cytosolic flagellin that rely on the Nlrc4 inflammasome.