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Lipopolysaccharide stimulates platelets through an IL-1? autocrine loop.


ABSTRACT: LPS activates platelets through TLR4, aiding productive sepsis, with stimulated splicing and translation of stored heteronuclear pro-IL-1? 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-1? and IL-1? stimulate heteronuclear I-1? splicing and translation of the newly made mRNA in platelets. Platelets also respond to the IL-1? 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-1? stimulates its own synthesis in an autocrine signaling loop. Strikingly, IL-1R antagonist inhibition, pharmacologic or genetic suppression of pro-IL-1? processing to active cytokine by caspase-1, or blockade of de novo protein synthesis also blocked LPS-induced IL-1? mRNA production. Robust stimulation of platelets by LPS therefore also required IL-1? amplification. Activated platelets made IL-1? in vivo as IL-1? rapidly accumulated in occluded murine carotid arteries by posttranscriptional RNA splicing unique to platelets. We conclude that IL-1? is a platelet agonist, that IL-1? acts through an autocrine stimulatory loop, that an IL-1? autocrine loop is required to amplify platelet activation by LPS, and that platelets immobilized in occlusive thrombi are activated over time to produce IL-1?. IL-1 is a new platelet agonist that promotes its own synthesis, connecting thrombosis with immunity.

SUBMITTER: Brown GT 

PROVIDER: S-EPMC3818355 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Lipopolysaccharide stimulates platelets through an IL-1β autocrine loop.

Brown G Thomas GT   Narayanan Padmini P   Li Wei W   Silverstein Roy L RL   McIntyre Thomas M TM  

Journal of immunology (Baltimore, Md. : 1950) 20130930 10


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  ...[more]

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