Activated platelets mediate inflammatory signaling by regulated interleukin 1beta synthesis.
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 1beta precursor (pro-IL-1beta). Unexpectedly, the mRNA for IL-1beta 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-1beta protein, a response that is abolished by translational inhibitors. A portion of the IL-1beta 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 beta3 integrin engagement markedly attenuated the synthesis of IL-1beta, identifying a new link between the coagulation and inflammatory cascades, and suggesting that antithrombotic therapies may also have novel antiinflammatory effects.
Lindemann
S
S
Department of Internal Medicine, University of Utah, Salt Lake City, UT 84112, USA.
Tolley
N D
ND
Dixon
D A
DA
McIntyre
T M
TM
Prescott
S M
SM
Zimmerman
G A
GA
Weyrich
A S
AS
D015703:Antigens, CD / Q000502:physiology; D001777:Blood Coagulation / Q000276:immunology; D002448:Cell Adhesion / Q000276:immunology; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology; D005337:Fibrin / Q000502:physiology; D015870:Gene Expression / Q000276:immunology; D006801:Humans; D039661:Integrin beta3; D007375:Interleukin-1 / Q000235:genetics* / Q000276:immunology*; D009504:Neutrophils / Q000166:cytology / Q000276:immunology; D015539:Platelet Activation / Q000276:immunology*; D010980:Platelet Membrane Glycoproteins / Q000502:physiology; D011132:Polyribosomes / Q000235:genetics; D014176:Protein Biosynthesis / Q000276:immunology; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction / Q000276:immunology*
D015703:Antigens, CD; D039661:Integrin beta3; D007375:Interleukin-1; D010980:Platelet Membrane Glycoproteins; D012333:RNA, Messenger; D005337:Fibrin