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Am J Physiol Cell Physiol (December 24, 2003). doi:10.1152/ajpcell.00494.2003
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Submitted on November 10, 2003
Accepted on December 12, 2003

Mechanisms of Caspase-1 Activation by P2X7 Receptor-Mediated K+ Release

J. Michelle Kahlenberg1 and George R Dubyak2*

1 Department of Pathology, Case School of Medicine, Cleveland, Ohio, USA
2 Department of Physiology and Biophysics, Case School of Medicine, Cleveland, Ohio, USA

* To whom correspondence should be addressed. E-mail: george.dubyak{at}case.edu.

The mechanisms underlying caspase-1 activation and IL-1{beta} processing during inflammatory activation of monocytes and macrophages are not well defined. Here, we describe an in vitro proteolytic processing assay that allows for comparison of caspase-1 regulatory components in a cell-free system separately from the confounding issue of IL-1{beta} secretion. Analysis of in vitro IL-1{beta} and caspase-1 processing in lysates from unstimulated Bac1 murine macrophages indicated a slow rate of basal caspase-1 activation and proteolytic maturation of IL-1{beta}. In contrast, brief (5 min) treatment of intact macrophages with extracellular ATP (as an activator of the P2X7 receptor) or nigericin before cell lysis markedly accelerated the in vitro processing of caspase-1 and IL-1{beta}. This acceleration of in vitro processing was strictly dependent on loss of intracellular K+ from the intact cells. The induction of in vitro caspase-1 activation by either lysis per se or by K+ loss prior to lysis was sensitive to pre-treatment of intact macrophages with the tyrphostin AG126 or bromoenol lactone (BEL), an inhibitor of Ca++-independent phospholipase A2. Caspase-1 activation and IL-1{beta} processing in lysates from unstimulated macrophages was similarly accelerated by addition of recombinant ASC, a previously identified adapter protein that directly associates with caspase-1. These data indicate that increased K+ efflux via P2X7 nucleotide receptor stimulation activates AG126 and BEL sensitive signaling pathways in murine macrophages that result in stably maintained signals for caspase-1 regulation in cell-free assays.




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