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Originally published In Press as doi:10.1074/jbc.M610762200 on May 9, 2007
J. Biol. Chem., Vol. 282, Issue 26, 18810-18818, June 29, 2007
Differential Requirement of P2X7 Receptor and Intracellular K+ for Caspase-1 Activation Induced by Intracellular and Extracellular Bacteria*
Luigi Franchi 1,
Thirumala-Devi Kanneganti ,
George R. Dubyak , and
Gabriel Núñez 2
From the
Department of Pathology and Comprehensive Cancer Center, The University of Michigan Medical School, Ann Arbor, Michigan 48109 and the Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106
Interleukin-1 (IL-1 ) is a pro-inflammatory cytokine that plays an important role in host defense and inflammatory diseases. The maturation and secretion of IL-1 are mediated by caspase-1, a protease that processes pro-IL-1 into biologically active IL-1 . The activity of caspase-1 is controlled by the inflammasome, a multiprotein complex formed by NLR proteins and the adaptor ASC, that induces the activation of caspase-1. The current model proposes that changes in the intracellular concentration of K+ potentiate caspase-1 activation induced by the recognition of bacterial products. However, the roles of P2X7 receptor and intracellular K+ in IL-1 secretion induced by bacterial infection remain unknown. Here we show that, in response to Toll-like receptor agonists such as lipopolysaccharide or infection with extracellular bacteria Staphylococcus aureus and Escherichia coli, efficient caspase-1 activation is only triggered by addition of ATP, a signal that promotes caspase-1 activation through depletion of intracellular K+ caused by stimulation of the purinergic P2X7 receptor. In contrast, activation of caspase-1 that relies on cytosolic sensing of flagellin or intracellular bacteria did not require ATP stimulation or depletion of cytoplasmic K+. Consistently, caspase-1 activation induced by intracellular Salmonella or Listeria was unimpaired in macrophages deficient in P2X7 receptor. These results indicate that, unlike caspase-1 induced by Toll-like receptor agonists and ATP, activation of the inflammasome by intracellular bacteria and cytosolic flagellin proceeds normally in the absence of P2X7 receptor-mediated cytoplasmic K+ perturbations.
Received for publication, November 20, 2006
, and in revised form, April 5, 2007.
* This work was supported in part by National Institutes of Health Grants AI063331, AR051790, and AI064748 (to G. N.) and GM36387 (to G. R. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 Recipient of a postdoctoral fellowship from the Arthritis Foundation.
2 To whom correspondence should be addressed: University of Michigan Medical School, 1500 E. Medical Center Dr., Ann Arbor, MI 48109. Tel.: 734-764-8514; Fax: 734-647-9654; E-mail: bclx{at}umich.ed.

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Copyright © 2007 by the American Society for Biochemistry and Molecular Biology.
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