Paracrine up-regulation of monocyte cyclooxygenase-2 by platelets : role of TGF-beta1

Introduction. Cellular interactions between platelets and leukocytes provide a crucial mechanism for intercellular communication in thrombosis and inflammation. We have examined the role of platelets and platelet-derived products on cyclooxygenase-2 (Cox-2) induction in adherent monocytes and addressed the signaling pathways involved. Methods. Human monocytes were co-cultured with autologous platelets or platelet releasates or exposed to mediators contained in platelet alphagranules for 4-24 h. Cox-2 protein and mRNA were determined by Western and RT-PCR. Thromboxane B2 and prostaglandin E2 synthesis as index of Cox-2 activity, and levels of TGF-b1 in platelet releasates were measured by EIA. Results. Activated platelets induce rapid and transient Cox-2 de novo synthesis in adherent monocytes. The effect is dependent upon platelet number but not upon cell-cell contact. Platelet-induced Cox-2 was not affected by prevention of platelet TxA2 synthesis or microparticle formation but was blunted by inhibition of platelet alphagranule secretion. TGF-b1 induced Cox-2 expression and activity at concentrations within the range of those detected in releasates from activated platelets. The time course of monocyte Cox-2 induction by TGF-b1 was identical to that observed with platelet releasates. Moreover, TGF- b1 receptor blockade completely abolished platelet-induced Cox-2 expression. p38 MAPK activation represents a common transduction pathway through which activated platelets and rTGF-b1 induce Cox-2 in monocytes. Conclusions. Data suggest that TGF-b1 released by activated platelets is pivotal in Cox-2 induction in monocytes and further supports the key role of platelets in inflammatory and reparative responses