ACTIVATED PLATELETS SIGNAL CHEMOKINE SYNTHESIS BY HUMAN MONOCYTES

Human blood monocytes adhere rapidly and for prolonged periods to acti vated platelets that display P-selectin, an adhesion protein that reco gnizes a specific ligand on leukocytes, P-selectin glycoprotein-l. We previously demonstrated that P-selectin regulates expression and secre tion of cytokines by stimulated monocytes when it is presented in a pu rified, immobilized form or by transfected cells. Here we show that th rombin-activated platelets induce the expression and secretion of mono cyte chemotactic protein-1 and IL-8 by monocytes. Enhanced monokine sy nthesis requires engagement of P-selectin glycoprotein-l on the leukoc yte by P-selectin on the platelet. Secretion of the chemokines is not, however, directly signaled by P-selectin; instead, tethering of the m onocytes by P-selectin is required for their activation by RANTES (reg ulated upon activation normal T cell expressed presumed secreted), a p latelet chemokine not previously known to induce immediate-early gene products in monocytes. Adhesion of monocytes to activated platelets re sults in nuclear translocation of p65 (RelA), a component of the NF-KB family of transcription factors that binds KB sequences in the regula tory regions of monocyte chemotactic protein-1, IL-8, and other immedi ate-early genes. However, expression of tissue factor, a coagulation p rotein that also has a KB sequence in the 5' regulatory region of its gene, is not induced in monocytes adherent to activated platelets. Thu s, contact of monocytes with activated platelets differentially affect s the expression of monocyte products. These experiments suggest that activated platelets regulate chemokine secretion by monocytes in infla mmatory lesions in vivo and provide a model for the study of gene regu lation in cell-cell interactions.