Expression of COX-2 in platelet-monocyte interactions occurs via combinatorial regulation involving adhesion and cytokine signaling.
Tight regulation of COX-2 expression is a key feature controlling eicosanoid production in atherosclerosis and other inflammatory syndromes. Adhesive interactions between platelets and monocytes occur in these conditions and deliver specific signals that trigger inflammatory gene expression. Using a cellular model of monocyte signaling induced by activated human platelets, we identified the central posttranscriptional mechanisms that regulate timing and magnitude of COX-2 expression. Tethering of monocytes to platelets and to purified P-selectin, a key adhesion molecule displayed by activated platelets, induces NF-kappaB activation and COX-2 promoter activity. Nevertheless, COX-2 mRNA is rapidly degraded, leading to aborted protein synthesis. Time-dependent signaling of monocytes induces a second phase of transcript accumulation accompanied by COX-2 enzyme synthesis and eicosanoid production. Here, generation of IL-1beta, a proinflammatory cytokine, promoted stabilization of COX-2 mRNA by silencing of the AU-rich mRNA decay element (ARE) in the 3'-untranslated region (3'UTR) of the mRNA. Consistent with observed mRNA stabilization, activated platelets or IL-1beta treatment induced cytoplasmic accumulation and enhanced ARE binding of the mRNA stability factor HuR in monocytes. These findings demonstrate that activated platelets induce COX-2 synthesis in monocytes by combinatorial signaling to transcriptional and posttranscriptional checkpoints. These checkpoints may be altered in disease and therefore useful as targets for antiinflammatory intervention.
Dixon
Dan A
DA
Department of Biological Sciences and South Carolina Cancer Center, University of South Carolina, Columbia, South Carolina 29203, USA. ddixon@biol.sc.edu
Tolley
Neal D
ND
Bemis-Standoli
Kristi
K
Martinez
Mark L
ML
Weyrich
Andrew S
AS
Morrow
Jason D
JD
Prescott
Stephen M
SM
Zimmerman
Guy A
GA
D020413:3' Untranslated Regions / Q000235:genetics; D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000954:Antigens, Surface / Q000378:metabolism; D001792:Blood Platelets / Q000166:cytology / Q000378:metabolism*; D002448:Cell Adhesion / Q000235:genetics / Q000502:physiology; D002450:Cell Communication / Q000235:genetics / Q000502:physiology*; D051546:Cyclooxygenase 2 / Q000235:genetics*; D016207:Cytokines / Q000378:metabolism* / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics*; D009000:Monocytes / Q000166:cytology / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D019007:P-Selectin / Q000494:pharmacology; D015539:Platelet Activation / Q000502:physiology; D039102:Poly(A)-Binding Proteins / Q000378:metabolism; D020871:RNA Stability / Q000187:drug effects; D016601:RNA-Binding Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D000074019:T-Cell Intracellular Antigen-1; D013917:Thrombin / Q000494:pharmacology; D014162:Transfection; D020298:U937 Cells; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D020413:3' Untranslated Regions; D000954:Antigens, Surface; D016207:Cytokines; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D008565:Membrane Proteins; D016328:NF-kappa B; D019007:P-Selectin; D039102:Poly(A)-Binding Proteins; D016601:RNA-Binding Proteins; D000074019:T-Cell Intracellular Antigen-1; C071558:TIA1 protein, human; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D013917:Thrombin; D015232:Dinoprostone