Expression of COX-2 in platelet-monocyte interactions occurs via combinatorial regulation involving adhesion and cytokine signaling
| Autor: | Stephen M. Prescott, Dan A. Dixon, Neal D. Tolley, Jason D. Morrow, Guy A. Zimmerman, Andrew S. Weyrich, Mark L. Martinez, Kristi Bemis-Standoli |
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| Rok vydání: | 2005 |
| Předmět: |
Blood Platelets
Cell signaling RNA Stability Interleukin-1beta Active Transport Cell Nucleus Cell Communication Transfection Poly(A)-Binding Proteins p38 Mitogen-Activated Protein Kinases Dinoprostone Gene Expression Regulation Enzymologic Monocytes Proinflammatory cytokine ELAV-Like Protein 1 Poly(A)-binding protein Cell Adhesion Gene silencing Humans Platelet activation Extracellular Signal-Regulated MAP Kinases 3' Untranslated Regions U937 cell biology NF-kappa B Thrombin Membrane Proteins RNA-Binding Proteins General Medicine MRNA stabilization U937 Cells Platelet Activation Molecular biology Cell biology T-Cell Intracellular Antigen-1 Interleukin 1 Receptor Antagonist Protein P-Selectin ELAV Proteins Cyclooxygenase 2 Antigens Surface biology.protein Cytokines Signal transduction Signal Transduction Research Article |
| Zdroj: | The Journal of clinical investigation. 116(10) |
| ISSN: | 0021-9738 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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