Activated platelets signal chemokine synthesis by human monocytes.

TLDR

Human blood monocytes rapidly adhere to activated platelets through P‑selectin/P‑selectin glycoprotein‑1 interactions, a contact previously shown to regulate cytokine expression in stimulated monocytes. Monocyte chemokine production is triggered when P‑selectin‑mediated adhesion to activated platelets permits RANTES to activate NF‑κB signaling, resulting in nuclear translocation of p65 and transcription of MCP‑1 and IL‑8. Thrombin‑activated platelets stimulate monocytes to secrete MCP‑1 and IL‑8, but not tissue factor, indicating that platelet–monocyte contact selectively upregulates chemokine production in inflammatory settings.

Abstract

Human blood monocytes adhere rapidly and for prolonged periods to activated platelets that display P-selectin, an adhesion protein that recognizes a specific ligand on leukocytes, P-selectin glycoprotein-1. We previously demonstrated that P-selectin regulates expression and secretion of cytokines by stimulated monocytes when it is presented in a purified, immobilized form or by transfected cells. Here we show that thrombin-activated platelets induce the expression and secretion of monocyte chemotactic protein-1 and IL-8 by monocytes. Enhanced monokine synthesis requires engagement of P-selectin glycoprotein-1 on the leukocyte by P-selectin on the platelet. Secretion of the chemokines is not, however, directly signaled by P-selectin; instead, tethering of the monocytes by P-selectin is required for their activation by RANTES (regulated upon activation normal T cell expressed presumed secreted), a platelet chemokine not previously known to induce immediate-early gene products in monocytes. Adhesion of monocytes to activated platelets results in nuclear translocation of p65 (RelA), a component of the NF-kappaB family of transcription factors that binds kappaB sequences in the regulatory regions of monocyte chemotactic protein-1, IL-8, and other immediate-early genes. However, expression of tissue factor, a coagulation protein that also has a kappaB sequence in the 5' regulatory region of its gene, is not induced in monocytes adherent to activated platelets. Thus, contact of monocytes with activated platelets differentially affects the expression of monocyte products. These experiments suggest that activated platelets regulate chemokine secretion by monocytes in inflammatory lesions in vivo and provide a model for the study of gene regulation in cell-cell interactions.