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Expression of COX-2 in platelet-monocyte interactions occurs via combinatorial regulation involving adhesion and cytokine signaling
Dan A. Dixon, … , Stephen M. Prescott, Guy A. Zimmerman
Dan A. Dixon, … , Stephen M. Prescott, Guy A. Zimmerman
Published October 2, 2006
Citation Information: J Clin Invest. 2006;116(10):2727-2738. https://doi.org/10.1172/JCI27209.
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Research Article Inflammation

Expression of COX-2 in platelet-monocyte interactions occurs via combinatorial regulation involving adhesion and cytokine signaling

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Abstract

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-κB 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-1β, 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-1β 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.

Authors

Dan A. Dixon, Neal D. Tolley, Kristi Bemis-Standoli, Mark L. Martinez, Andrew S. Weyrich, Jason D. Morrow, Stephen M. Prescott, Guy A. Zimmerman

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Figure 1

Activated platelets induce COX-2 expression in monocytes.

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Activated platelets induce COX-2 expression in monocytes.
(A) Activation...
(A) Activation of platelets (plts) is required for COX-2 mRNA (left panel) and protein (right panel) expression. Monocytes (106 cells) were incubated with control M199 medium (co), thrombin (IIa), inactivated platelets (108 cells), or thrombin-activated platelets. After 18 hours, COX-2 mRNA was detected by RNase protection assays. GAPDH mRNA is shown as a control for RNA loading. COX-2 protein was detected by immunoblot of 50 μg of total cell lysate. β-actin was detected on the same blot as a control for protein loading. Data shown represent 3 experiments. (B) Immunofluorescent detection of COX-2 and P-selectin in thrombin-activated platelet-monocyte aggregates. Freshly isolated platelets were incubated with monocytes for 18 hours and examined by immunocytochemical analysis. Immunofluorescent staining for COX-2 is shown in red (top right); immunofluorescent staining for P-selectin, a platelet marker, is shown in green (top left). Merged immunofluorescence and phase contrast images are shown (bottom left and right). (C) COX activity in monocytes (mono) and monocyte/platelet suspensions (mono+plts) treated with medium (co) or thrombin (IIa) for 18 hours. COX-2 inhibition was accomplished by pretreating cells for 1 hour with 10 μM NS-398 (NS). PGE2 levels were measured by ELISA in the medium containing arachidonic acid and indicate the average of duplicate experiments.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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