Home LiteratureArticle Details
PMID: 18523012 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 105 ·No. 23 ·2008-06-10 ·Pages 8067-72

Piccini A, Carta S, Tassi S, Lasiglié D, Fossati G, Rubartelli A

Abstract

IL-1beta and IL-18 are crucial mediators of inflammation, and a defective control of their release may cause serious diseases. Yet, the mechanisms regulating IL-1beta 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-1beta 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 P2X(7). Indeed, antagonists of the P2X(7) receptor (P2X(7)R), or treatment with apyrase, prevent IL-1beta and IL-18 maturation and secretion triggered by the different stimuli. At variance, blocking P2X(7)R activity has no effects on IL-1beta secretion by monocytes carrying a mutated inflammasome that does not require exogenous ATP for activation. P2X(7)R 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-1beta and IL-18 secretion.

MeSH Terms
Adenosine Triphosphate/metabolism Autocrine Communication/drug effects Cells, Cultured Enzyme Inhibitors/pharmacology Histone Deacetylase Inhibitors Humans Interleukin-18/metabolism Interleukin-1beta/metabolism Kinetics Ligands Monocytes/drug effects,metabolism Phospholipase A2 Inhibitors Potassium/metabolism Protein Processing, Post-Translational/drug effects Receptors, Pattern Recognition/metabolism Receptors, Purinergic P2/metabolism Receptors, Purinergic P2X7 Toll-Like Receptors/metabolism
Chemicals
Enzyme Inhibitors Histone Deacetylase Inhibitors Interleukin-18 Interleukin-1beta Ligands P2RX7 protein, human Phospholipase A2 Inhibitors Receptors, Pattern Recognition Receptors, Purinergic P2 Receptors, Purinergic P2X7 Toll-Like Receptors Adenosine Triphosphate Potassium
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Piccini Alessandra
Cell Biology Unit, National Cancer Research Institute, Largo Rosanna Benzi 10, 16132 Genoa, Italy. alessandra.piccini@istge.it
Carta Sonia
Tassi Sara
Lasiglié Denise
Fossati Gianluca
Rubartelli Anna
References (47)
47 references, click to expand
  1. Differential requirement of P2X7 receptor and intracellular K+ for caspase-1 activation induced by intracellular and extracellular bacteria.
    J Biol Chem. 2007 Jun 29;282(26):18810-8 PMID: 17491021
  2. Intracellular pattern recognition receptors in the host response.
    Nature. 2006 Jul 6;442(7098):39-44 PMID: 16823444
  3. Gout-associated uric acid crystals activate the NALP3 inflammasome.
    Nature. 2006 Mar 9;440(7081):237-41 PMID: 16407889
  4. Yeast zymosan, a stimulus for TLR2 and dectin-1, induces regulatory antigen-presenting cells and immunological tolerance.
    J Clin Invest. 2006 Apr;116(4):916-28 PMID: 16543948
  5. Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3.
    Nature. 2006 Mar 9;440(7081):233-6 PMID: 16407888
  6. OppA, the substrate-binding subunit of the oligopeptide permease, is the major Ecto-ATPase of Mycoplasma hominis.
    J Bacteriol. 2004 Feb;186(4):1021-928 PMID: 14761996
  7. CD39/NTPDase-1 activity and expression in normal leukocytes.
    Thromb Res. 2007;121(3):309-17 PMID: 17555802
  8. Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1beta via Ipaf.
    Nat Immunol. 2006 Jun;7(6):569-75 PMID: 16648853
  9. Oxidized ATP. An irreversible inhibitor of the macrophage purinergic P2Z receptor.
    J Biol Chem. 1993 Apr 15;268(11):8199-203 PMID: 8463330
  10. Pannexin-1-mediated recognition of bacterial molecules activates the cryopyrin inflammasome independent of Toll-like receptor signaling.
    Immunity. 2007 Apr;26(4):433-43 PMID: 17433728
  11. Interleukin-1, interleukin-1 receptors and interleukin-1 receptor antagonist.
    Int Rev Immunol. 1998;16(5-6):457-99 PMID: 9646173
  12. Potassium regulates IL-1 beta processing via calcium-independent phospholipase A2.
    J Immunol. 2000 May 15;164(10):5120-4 PMID: 10799869
  13. Ca2+/calmodulin-dependent kinase II and calcineurin play critical roles in endothelin-1-induced cardiomyocyte hypertrophy.
    J Biol Chem. 2000 May 19;275(20):15239-45 PMID: 10809760
  14. The P2X7 receptor: a key player in IL-1 processing and release.
    J Immunol. 2006 Apr 1;176(7):3877-83 PMID: 16547218
  15. A novel secretory pathway for interleukin-1 beta, a protein lacking a signal sequence.
    EMBO J. 1990 May;9(5):1503-10 PMID: 2328723
  16. Critical role for NALP3/CIAS1/Cryopyrin in innate and adaptive immunity through its regulation of caspase-1.
    Immunity. 2006 Mar;24(3):317-27 PMID: 16546100
  17. Reconstituted NALP1 inflammasome reveals two-step mechanism of caspase-1 activation.
    Mol Cell. 2007 Mar 9;25(5):713-24 PMID: 17349957
  18. The relationship between constitutive ATP release and its extracellular metabolism in isolated rat kidney glomeruli.
    J Physiol Pharmacol. 2007 Jun;58(2):321-33 PMID: 17622700
  19. Cryopyrin activates the inflammasome in response to toxins and ATP.
    Nature. 2006 Mar 9;440(7081):228-32 PMID: 16407890
  20. Inflammasome adaptors and sensors: intracellular regulators of infection and inflammation.
    Nat Rev Immunol. 2007 Jan;7(1):31-40 PMID: 17186029
  21. Cutting edge: TLR2-deficient and MyD88-deficient mice are highly susceptible to Staphylococcus aureus infection.
    J Immunol. 2000 Nov 15;165(10):5392-6 PMID: 11067888
  22. NK/iDC interaction results in IL-18 secretion by DCs at the synaptic cleft followed by NK cell activation and release of the DC maturation factor HMGB1.
    Blood. 2005 Jul 15;106(2):609-16 PMID: 15802534
  23. Colocalization of ATP release sites and ecto-ATPase activity at the extracellular surface of human astrocytes.
    J Biol Chem. 2003 Jun 27;278(26):23331-42 PMID: 12684505
  24. Phospholipases C and A2 control lysosome-mediated IL-1 beta secretion: Implications for inflammatory processes.
    Proc Natl Acad Sci U S A. 2004 Jun 29;101(26):9745-50 PMID: 15192144
  25. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5.
    Nature. 2001 Apr 26;410(6832):1099-103 PMID: 11323673
  26. Pattern of interleukin-1beta secretion in response to lipopolysaccharide and ATP before and after interleukin-1 blockade in patients with CIAS1 mutations.
    Arthritis Rheum. 2007 Sep;56(9):3138-48 PMID: 17763411
  27. Identification of bacterial muramyl dipeptide as activator of the NALP3/cryopyrin inflammasome.
    Curr Biol. 2004 Nov 9;14(21):1929-34 PMID: 15530394
  28. Interleukin-18 and the pathogenesis of inflammatory diseases.
    Semin Nephrol. 2007 Jan;27(1):98-114 PMID: 17336692
  29. Purinergic modulation of interleukin-1 beta release from microglial cells stimulated with bacterial endotoxin.
    J Exp Med. 1997 Feb 3;185(3):579-82 PMID: 9053458
  30. Potassium-inhibited processing of IL-1 beta in human monocytes.
    EMBO J. 1995 Apr 18;14(8):1607-14 PMID: 7737113
  31. Inside, outside, upside down: damage-associated molecular-pattern molecules (DAMPs) and redox.
    Trends Immunol. 2007 Oct;28(10):429-36 PMID: 17845865
  32. Toll-like receptors; their physiological role and signal transduction system.
    Int Immunopharmacol. 2001 Apr;1(4):625-35 PMID: 11357875
  33. Protein kinase D interaction with TLR5 is required for inflammatory signaling in response to bacterial flagellin.
    J Immunol. 2007 May 1;178(9):5735-43 PMID: 17442957
  34. Engagement of NOD2 has a dual effect on proIL-1beta mRNA transcription and secretion of bioactive IL-1beta.
    Eur J Immunol. 2008 Jan;38(1):184-91 PMID: 18157816
  35. Interleukin-1 beta maturation and release in response to ATP and nigericin. Evidence that potassium depletion mediated by these agents is a necessary and common feature of their activity.
    J Biol Chem. 1994 May 27;269(21):15195-203 PMID: 8195155
  36. Inflammatory caspases and inflammasomes: master switches of inflammation.
    Cell Death Differ. 2007 Jan;14(1):10-22 PMID: 16977329
  37. A novel P2X7 receptor activator, the human cathelicidin-derived peptide LL37, induces IL-1 beta processing and release.
    J Immunol. 2004 Apr 15;172(8):4987-94 PMID: 15067080
  38. The secretory route of the leaderless protein interleukin 1beta involves exocytosis of endolysosome-related vesicles.
    Mol Biol Cell. 1999 May;10(5):1463-75 PMID: 10233156
  39. IL-18 in autoimmunity: review.
    Eur Cytokine Netw. 2006 Dec;17(4):224-52 PMID: 17353157
  40. Toll-like receptor signalling.
    Nat Rev Immunol. 2004 Jul;4(7):499-511 PMID: 15229469
  41. Histone deacetylase inhibitors prevent exocytosis of interleukin-1beta-containing secretory lysosomes: role of microtubules.
    Blood. 2006 Sep 1;108(5):1618-26 PMID: 16684958
  42. Isoquinolines as antagonists of the P2X7 nucleotide receptor: high selectivity for the human versus rat receptor homologues.
    Mol Pharmacol. 1998 Jul;54(1):22-32 PMID: 9658186
  43. The inflammasome in pathogen recognition and inflammation.
    J Leukoc Biol. 2007 Aug;82(2):259-64 PMID: 17470531
  44. Nod-like proteins in immunity, inflammation and disease.
    Nat Immunol. 2006 Dec;7(12):1250-7 PMID: 17110941
  45. Interleukin-18 synthesis and secretion by dendritic cells are modulated by interaction with antigen-specific T cells.
    J Leukoc Biol. 1999 Aug;66(2):237-41 PMID: 10449160
  46. Critical role of toll-like receptors and nucleotide oligomerisation domain in the regulation of health and disease.
    J Endocrinol. 2007 Jun;193(3):323-30 PMID: 17535871
  47. Early events in the recognition of danger signals after tissue injury.
    J Leukoc Biol. 2008 Mar;83(3):546-52 PMID: 18032691
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.0709684105
Email
alessandra.piccini@istge.it
Published
2008-06-10
Epub
2008-00-03
Pages
8067-72
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC2430360
Subset
IM
Grants
Telethon · GGP06009 · Italy
External Links
PubMed source DOI: 10.1073/pnas.0709684105 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2