Thrombin receptor activation inhibits monocyte spreading by induction of ET(B) receptor-coupled nitric oxide release.
The effect of thrombin receptor activation on monocyte conformation was evaluated using the human monocyte cell line, THP-1, and the thrombin mimetic peptide, Trap-14. Treatment of THP-1 cells with Trap-14 induced rapid rounding of ameboid cells adherent to fibronectin-coated slides, whereas cell rounding was abrogated in the presence of the nitric oxide synthase inhibitor, NG-nitro-L-arginine or the endothelin B receptor antagonist, BQ-788. Endothelin-1 (ET-1) levels in the culture supernatant increased markedly within minutes of Trap-14 exposure with a concomitant loss in cellular ET-1 immunoreactivity. Importantly, loss of ET-1 immunoreactivity was blocked by pretreatment with the vesicle translocation inhibitor, nocodazole. Trap-14 potently induced the release of NO from THP-1 cells, whereas NO release was ablated by preincubation with BQ-788. These data demonstrate that thrombin receptor activation may inhibit cellular spreading as a result of autocrine ET-1 release and subsequent endothelin B receptor-dependent NO production, and suggest that initial exposure of inflammatory cells to thrombin may limit cellular activation and recruitment.
Srivastava
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Department of Biology, Queens College and Graduate School, City University of New York, Flushing 11367, USA.
Magazine
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D002448:Cell Adhesion / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D006801:Humans; D007948:Leukemia, Monocytic, Acute / Q000473:pathology; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000502:physiology*; D015739:Nocodazole / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000502:physiology*; D018179:Receptors, Thrombin / Q000187:drug effects / Q000502:physiology*; D013917:Thrombin / Q000494:pharmacology / Q000502:physiology; D014407:Tumor Cells, Cultured
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D009842:Oligopeptides; D010446:Peptide Fragments; D010880:Piperidines; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D018179:Receptors, Thrombin; C072032:thrombin receptor peptide (42-55); D009569:Nitric Oxide; C086539:BQ 788; D013917:Thrombin; D015739:Nocodazole