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¹ Department of Internal Medicine, University of Utah, Salt Lake City, UT 84112
² Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112
³ Department of Pathology, University of Utah, Salt Lake City, UT 84112
⁴ Program in Human Molecular Biology and Genetics, University of Utah, Salt Lake City, UT 84112
⁵ Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112

Address correspondence to Andrew S. Weyrich, Program in Human Molecular Biology and Genetics, University of Utah, 15 North 2030 East, Bldg. 533, Rm. 4220, Salt Lake City, UT 84112. Tel.: (801) 585-0702. Fax: (801) 585-0701. E-mail: andy.weyrich{at}hmbg.utah.edu

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 1ß precursor (pro–IL-1ß). Unexpectedly, the mRNA for IL-1ß 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-1ß protein, a response that is abolished by translational inhibitors. A portion of the IL-1ß 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 ß₃ integrin engagement markedly attenuated the synthesis of IL-1ß, identifying a new link between the coagulation and inflammatory cascades, and suggesting that antithrombotic therapies may also have novel antiinflammatory effects.

Key Words: adhesion; cytokines; integrins; platelets; translation

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