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Papers In Press, published online ahead of print May 9, 2007
Pathology, University of Michigan Med School, Ann Arbor, MI 48109
Corresponding Author: bclx{at}umich.edu
IL-1b is a proinflammatory cytokine that plays an important role in host defense and inflammatory diseases. The maturation and secretion of IL-1b is mediated by caspase-1, a protease that processes pro-IL-1b into biologically active IL-1b. 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 role of P2X7 receptor and intracellular K+ in IL-1bsecretion induced by bacterial infection remains unknown. Here we show that in response to TLR agonists such as LPS or infection with extracellular bacteria S. aureus and E. 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 TLR 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.
J. Biol. Chem, 10.1074/jbc.M610762200
Submitted on November 20, 2006
Revised on April 5, 2007
Accepted on May 9, 2007
Differential requirement of P2X7 receptor and intracellular K+ for caspase-1 activation induced by intracellular and extracellular bacteria
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