Activated platelets mediate inflammatory signaling by regulated interleukin 1β synthesis

TLDR

Platelets release preformed mediators and eicosanoids that regulate hemostasis and inflammation, yet they were not believed to synthesize proteins or cytokines or modulate inflammatory responses over time. A cDNA library screen revealed that quiescent platelets harbor numerous mRNAs, including one encoding the interleukin‑1β precursor. Platelets contain IL‑1β mRNA in polysomes, enabling rapid, activation‑driven synthesis of pro‑IL‑1β that is shed as mature cytokine in microvesicles, promotes endothelial neutrophil adhesion, and is attenuated by β3 integrin blockade, linking coagulation to inflammation and suggesting antithrombotic drugs may have anti‑inflammatory effects.

Abstract

Platelets release preformed mediators and generate eicosanoids that regulate acute hemostasis and inflammation, but these anucleate cytoplasts are not thought to synthesize proteins or cytokines, or to influence inflammatory responses over time. Interrogation of an arrayed cDNA library demonstrated that quiescent platelets contain many messenger RNAs, one of which codes for interleukin 1β precursor (pro–IL-1β). Unexpectedly, the mRNA for IL-1β and many other transcripts are constitutively present in polysomes, providing a mechanism for rapid synthesis. Platelet activation induces rapid and sustained synthesis of pro–IL-1β protein, a response that is abolished by translational inhibitors. A portion of the IL-1β is shed in its mature form in membrane microvesicles, and induces adhesiveness of human endothelial cells for neutrophils. Signal-dependent synthesis of an active cytokine over several hours indicates that platelets may have previously unrecognized roles in inflammation and vascular injury. Inhibition of β3 integrin engagement markedly attenuated the synthesis of IL-1β, identifying a new link between the coagulation and inflammatory cascades, and suggesting that antithrombotic therapies may also have novel antiinflammatory effects.