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Lipopolysaccharide Stimulates Platelets through an IL-1β Autocrine Loop

G. Thomas Brown, Padmini Narayanan, Wei Li, Roy L. Silverstein and Thomas M. McIntyre
J Immunol November 15, 2013, 191 (10) 5196-5203; DOI: https://doi.org/10.4049/jimmunol.1300354
G. Thomas Brown
*Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195; and
†Cell Biology Graduate Training Program, Medical Scientist Training Program, School of Medicine, Case Western Reserve University, Cleveland, OH 44106
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Padmini Narayanan
*Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195; and
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Wei Li
*Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195; and
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Roy L. Silverstein
*Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195; and
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Thomas M. McIntyre
*Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195; and
†Cell Biology Graduate Training Program, Medical Scientist Training Program, School of Medicine, Case Western Reserve University, Cleveland, OH 44106
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Abstract

LPS activates platelets through TLR4, aiding productive sepsis, with stimulated splicing and translation of stored heteronuclear pro–IL-1β RNA. Although the IL-1R type 1 (IL-1R1) receptor for IL-1 shares downstream components with the TLR4 receptor, platelets are not known to express IL-1R1, nor are they known to respond to this cytokine. We show by flow cytometry and Western blotting that platelets express IL-1R1, and that IL-1β and IL-1α stimulate heteronuclear I-1β splicing and translation of the newly made mRNA in platelets. Platelets also respond to the IL-1β they make, which is exclusively associated with shed microparticles. Specific blockade of IL-1R1 with IL-1R antagonist suppressed platelet stimulation by IL-1, so IL-1β stimulates its own synthesis in an autocrine signaling loop. Strikingly, IL-1R antagonist inhibition, pharmacologic or genetic suppression of pro–IL-1β processing to active cytokine by caspase-1, or blockade of de novo protein synthesis also blocked LPS-induced IL-1β mRNA production. Robust stimulation of platelets by LPS therefore also required IL-1β amplification. Activated platelets made IL-1β in vivo as IL-1β rapidly accumulated in occluded murine carotid arteries by posttranscriptional RNA splicing unique to platelets. We conclude that IL-1β is a platelet agonist, that IL-1β acts through an autocrine stimulatory loop, that an IL-1β autocrine loop is required to amplify platelet activation by LPS, and that platelets immobilized in occlusive thrombi are activated over time to produce IL-1β. IL-1 is a new platelet agonist that promotes its own synthesis, connecting thrombosis with immunity.

This article is featured in In This Issue, p.4891

Footnotes

  • This work was supported by National Institutes of Health Grants P50 HL081011 and 1 R01 HL092747 and by Case Western Reserve University/Cleveland Clinic Clinical and Translational Science Award UL1 RR024989 from the National Institutes of Health/National Center for Research Resources.

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article:

    hn
    heteronuclear
    IL-1R1
    IL-1R type 1
    IL-1Ra
    IL-1R antagonist
    LPB
    LPS binding protein
    TIR
    Toll/IL-1R
    TRAF
    TNFR-associated factor.

  • Received February 7, 2013.
  • Accepted September 5, 2013.
  • Copyright © 2013 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 191 (10)
The Journal of Immunology
Vol. 191, Issue 10
15 Nov 2013
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Lipopolysaccharide Stimulates Platelets through an IL-1β Autocrine Loop
G. Thomas Brown, Padmini Narayanan, Wei Li, Roy L. Silverstein, Thomas M. McIntyre
The Journal of Immunology November 15, 2013, 191 (10) 5196-5203; DOI: 10.4049/jimmunol.1300354

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Lipopolysaccharide Stimulates Platelets through an IL-1β Autocrine Loop
G. Thomas Brown, Padmini Narayanan, Wei Li, Roy L. Silverstein, Thomas M. McIntyre
The Journal of Immunology November 15, 2013, 191 (10) 5196-5203; DOI: 10.4049/jimmunol.1300354
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