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Am J Physiol Cell Physiol 286: C1100-C1108, 2004. First published December 24, 2003; doi:10.1152/ajpcell.00494.2003
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RECEPTORS AND SIGNAL TRANSDUCTION

Mechanisms of caspase-1 activation by P2X7 receptor-mediated K+ release

J. Michelle Kahlenberg1 and George R. Dubyak2

Departments of 1Pathology and 2Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106

Submitted 10 November 2003 ; accepted in final form 12 December 2003

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 lysis per se or by K+ loss before lysis was sensitive to pretreatment of intact macrophages with the tyrphostin AG-126 or bromoenol lactone, an inhibitor of Ca2+-independent phospholipase A2. Caspase-1 activation and IL-1{beta} processing in lysates from unstimulated macrophages were also 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 AG-126- and bromoenol lactone-sensitive signaling pathways in murine macrophages that result in stably maintained signals for caspase-1 regulation in cell-free assays.

AG-126; ASC; bromoenol lactone; IL-1{beta}; inflammation


Address for reprint requests and other correspondence: G. R. Dubyak, Dept. of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106 (E-mail: george.dubyak{at}case.edu).




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