Pyroptosis is a type of cell death in which danger associated molecular patterns (DAMPs) and pathogen associated molecular patterns (PAMPs) induce mononuclear phagocytes to activate caspase-1 and release mature IL-1 beta. Because the tyrosine kinase inhibitor AG126 can prevent DAMP/PAMP induced activation of caspase-1, we hypothesized that tipping the tyrosine kinase/phosphatase balance toward phosphorylation would promote caspase-1 activation and cell death. THP-1 derived macrophages were therefore treated with the potent specific tyrosine phosphatase inhibitor, sodium orthovanadate (OVN) and analyzed for caspase-1 activation and cell death. OVN induced generalized increase in phosphorylated proteins, IL-1 beta release and cell death in a time and dose dependent pattern. This OVN induced pyroptosis correlated with speck formations that contained the apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC). Culturing the cells in the presence of extracellular K+ (known to inhibit ATP dependent pyroptosis), a caspase inhibitor (ZVAD) or down regulating the expression of ASC with stable expression of siASC prevented the OVN induced pyroptosis. These data demonstrate that pyroptotic death is linked to tyrosine phosphatase activity providing novel targets for future pharmacologic interventions. (c) 2012 Elsevier Inc. All rights reserved.