THROMBIN RECEPTOR ACTIVATION INHIBITS MONOCYTE SPREADING BY INDUCTIONOF ETB RECEPTOR-COUPLED NITRIC-OXIDE RELEASE

The effect of thrombin receptor activation on monocyte conformation wa s evaluated using the human monocyte cell line, THP-1, and the thrombi n mimetic peptide, Trap-14, Treatment of THP-1 cells with Trap-14 indu ced rapid rounding of ameboid cells adherent to fibronectin-coated sli des, whereas cell rounding was abrogated in the presence of the nitric oxide synthase inhibitor, NG-nitro-L-arginine or the endothelin B rec eptor antagonist, BQ-788, Endothelin-l (ET-1) levels in the culture su pernatant 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 rel ease of NO from THP-1 cells, whereas NO release was ablated by preincu bation with BQ-788, These data demonstrate that thrombin receptor acti vation may inhibit cellular spreading as a result of autocrine ET-1 re lease and subsequent endothelin B receptor-dependent NO production, an d suggest that initial exposure of inflammatory cells to thrombin may limit cellular activation and recruitment.