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.
Mesh Terms:
3' Untranslated Regions, Active Transport, Cell Nucleus, Antigens, Surface, Blood Platelets, Cell Adhesion, Cell Communication, Cyclooxygenase 2, Cytokines, Dinoprostone, Extracellular Signal-Regulated MAP Kinases, Gene Expression Regulation, Enzymologic, Hu Paraneoplastic Encephalomyelitis Antigens, Humans, Interleukin 1 Receptor Antagonist Protein, Interleukin-1beta, Membrane Proteins, Monocytes, NF-kappa B, P-Selectin, Platelet Activation, Poly(A)-Binding Proteins, RNA Stability, RNA-Binding Proteins, Signal Transduction, Thrombin, Transfection, U937 Cells, p38 Mitogen-Activated Protein Kinases
3' Untranslated Regions, Active Transport, Cell Nucleus, Antigens, Surface, Blood Platelets, Cell Adhesion, Cell Communication, Cyclooxygenase 2, Cytokines, Dinoprostone, Extracellular Signal-Regulated MAP Kinases, Gene Expression Regulation, Enzymologic, Hu Paraneoplastic Encephalomyelitis Antigens, Humans, Interleukin 1 Receptor Antagonist Protein, Interleukin-1beta, Membrane Proteins, Monocytes, NF-kappa B, P-Selectin, Platelet Activation, Poly(A)-Binding Proteins, RNA Stability, RNA-Binding Proteins, Signal Transduction, Thrombin, Transfection, U937 Cells, p38 Mitogen-Activated Protein Kinases
J. Clin. Invest.
Date: Oct. 01, 2006
PubMed ID: 16998585
View in: Pubmed Google Scholar
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