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rdf:type |
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lifeskim:mentions |
umls-concept:C0007428,
umls-concept:C0022408,
umls-concept:C0024432,
umls-concept:C0030685,
umls-concept:C0391871,
umls-concept:C0441712,
umls-concept:C0444497,
umls-concept:C0680255,
umls-concept:C1283071,
umls-concept:C1314939,
umls-concept:C1963578
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pubmed:issue |
4
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pubmed:dateCreated |
2010-8-5
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pubmed:abstractText |
The ATP-gated P2X(7) receptor (P2X(7)R) is a promising therapeutic target in chronic inflammatory diseases with highly specific antagonists currently under clinical trials for rheumatoid arthritis. Anti-inflammatory actions of P2X(7)R antagonists are considered to result from inhibition of P2X(7)R-induced release of proinflammatory cytokines from activated macrophages. However, P2X(7)Rs are also expressed in resting macrophages, suggesting that P2X(7)R may also signal via cytokine-independent mechanisms involved in joint disease. In this study, we examined P2X(7)R function in resting human lung macrophages and mouse bone marrow-derived macrophages and found that ATP induced rapid release of the lysosomal cysteine proteases cathepsin B, K, L, and S and that was independent of the presence of the proinflammatory cytokines IL-1beta and IL-18. Cathepsins released into the medium were effective to degrade collagen extracellular matrix. ATP-induced cathepsin release was abolished by P2X(7)R antagonists, absent from P2X(7)R(-/-) mouse macrophages, and not associated with cell death. Our results suggest P2X(7)R activation may play a novel and direct role in tissue damage through release of cathepsins independently of its proinflammatory actions via IL-1 cytokines.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
AIM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/AZ 11645373,
http://linkedlifedata.com/resource/pubmed/chemical/Adenosine Triphosphate,
http://linkedlifedata.com/resource/pubmed/chemical/Cathepsin B,
http://linkedlifedata.com/resource/pubmed/chemical/Cathepsins,
http://linkedlifedata.com/resource/pubmed/chemical/Cytokines,
http://linkedlifedata.com/resource/pubmed/chemical/Immunoglobulin G,
http://linkedlifedata.com/resource/pubmed/chemical/Immunosuppressive Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Interleukin-1beta,
http://linkedlifedata.com/resource/pubmed/chemical/Methotrexate,
http://linkedlifedata.com/resource/pubmed/chemical/P2RX7 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/P2rx7 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Purinergic P2 Receptor Antagonists,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Purinergic P2,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Purinergic P2X7,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Tumor Necrosis Factor,
http://linkedlifedata.com/resource/pubmed/chemical/TNFR-Fc fusion protein,
http://linkedlifedata.com/resource/pubmed/chemical/Thiazoles
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pubmed:status |
MEDLINE
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pubmed:month |
Aug
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pubmed:issn |
1550-6606
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:day |
15
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pubmed:volume |
185
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
2611-9
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pubmed:dateRevised |
2010-11-18
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pubmed:meshHeading |
pubmed-meshheading:20639492-Adenosine Triphosphate,
pubmed-meshheading:20639492-Animals,
pubmed-meshheading:20639492-Blotting, Western,
pubmed-meshheading:20639492-Cathepsin B,
pubmed-meshheading:20639492-Cathepsins,
pubmed-meshheading:20639492-Cells, Cultured,
pubmed-meshheading:20639492-Cytokines,
pubmed-meshheading:20639492-Dose-Response Relationship, Drug,
pubmed-meshheading:20639492-Enzyme-Linked Immunosorbent Assay,
pubmed-meshheading:20639492-Humans,
pubmed-meshheading:20639492-Immunoglobulin G,
pubmed-meshheading:20639492-Immunosuppressive Agents,
pubmed-meshheading:20639492-Interleukin-1beta,
pubmed-meshheading:20639492-Joint Diseases,
pubmed-meshheading:20639492-L Cells (Cell Line),
pubmed-meshheading:20639492-Macrophages,
pubmed-meshheading:20639492-Methotrexate,
pubmed-meshheading:20639492-Mice,
pubmed-meshheading:20639492-Mice, Inbred C57BL,
pubmed-meshheading:20639492-Mice, Knockout,
pubmed-meshheading:20639492-Molecular Structure,
pubmed-meshheading:20639492-Purinergic P2 Receptor Antagonists,
pubmed-meshheading:20639492-Receptors, Purinergic P2,
pubmed-meshheading:20639492-Receptors, Purinergic P2X7,
pubmed-meshheading:20639492-Receptors, Tumor Necrosis Factor,
pubmed-meshheading:20639492-Thiazoles
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pubmed:year |
2010
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pubmed:articleTitle |
P2X(7) receptor-mediated release of cathepsins from macrophages is a cytokine-independent mechanism potentially involved in joint diseases.
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pubmed:affiliation |
Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom. gloria.lopez-castejon@manchester.ac.uk
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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