ATP is released by monocytes stimulated with pathogen-sensing receptor ligands and induces IL-1β and IL-18 secretion in an autocrine way

Alessandra Piccini, Sonia Carta, Sara Tassi, Denise Lasiglié, Gianluca Fossati, Anna Rubartelli

Research output: Contribution to journalArticlepeer-review

Abstract

IL-1β and IL-18 are crucial mediators of inflammation, and a defective control of their release may cause serious diseases. Yet, the mechanisms regulating IL-1β and IL-18 secretion are partially undefined. Both cytokines are produced as inactive cytoplasmic precursors. Processing to the active form is mediated by caspase-1, which is in turn activated by the multiprotein complex inflammasome. Here, we show that in primary human monocytes microbial components acting on different pathogen-sensing receptors and the danger-associated molecule uric acid are all competent to induce maturation and secretion of IL-1β and IL-18 through a process that involves as a first event the extracellular release of endogenous ATP. ATP release is followed by autocrine stimulation of the purinergic receptors P2X7. Indeed, antagonists of the P2X7 receptor (P2X7R), or treatment with apyrase, prevent IL-1β and IL-18 maturation and secretion triggered by the different stimuli. At variance, blocking P2X7R activity has no effects on IL-1β secretion by monocytes carrying a mutated inflammasome that does not require exogenous ATP for activation. P2X7R engagement is followed by K+ efflux and activation of phospholipase A 2. Both events are required for processing and secretion induced by all of the stimuli. Thus, stimuli acting on different pathogen-sensing receptors converge on a common pathway where ATP externalization is the first step in the cascade of events leading to inflammasome activation and IL-1β and IL-18 secretion.

Original languageEnglish
Pages (from-to)8067-8072
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number23
DOIs
Publication statusPublished - Jun 10 2008

Keywords

  • Inflammation
  • Nonclassical secretion
  • Pathogen-associated molecular patterns
  • Processing

ASJC Scopus subject areas

  • Genetics
  • General

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