Oncostatin M promotes biphasic tissue factor expression in smooth muscle cells: evidence for Erk-1/2 activation

Tissue factor (TF), a transmembrane glycoprotein, initiates the extrinsic c oagulation cascade, TF is known to play a major role in mediating thrombosi s and thrombotic episodes associated with the progression of atherosclerosi s. Macrophages at inflammatory sites, such as atherosclerotic lesions, rele ase numerous cytokines that are capable of modulating TF expression. This s tudy examined the role of oncostatin M (OSM), a macrophage/T-lymphocyte-res tricted cytokine, in the expression of TF in vascular smooth muscle cells ( SMCs), It is reported here that OSM stimulated a biphasic and sustained pat tern of TF messenger RNA (mRNA), The effect of OSM on TF mRNA expression wa s regulated at the transcriptional level as determined by nuclear runoffs a nd transient transfection of a TF promoter-reporter gene construct. OSM-ind uced TF expression was regulated primarily by the transcription factor NF-k appaB, Activation of NF-kappaB by OSM did not require I kappaB-alpha degrad ation, Inhibition of MEK activity by U0126 prevented OSM-induced TF express ion by suppressing NF-kappaB DNA binding activity as determined by gel-shif t analysis, Further, inhibition of Erk-1/2 protein by antisense treatment r esulted in suppression of TF mRNA expression, indicating a role for Erk-1/2 in modulating NF-kappaB DNA binding activity, These studies suggest that t he induced expression of TF by OSM is primarily through the activation of N F-kappaB and that activation of NF-kappaB is regulated in part by the MEK/E rk-1/2 signal transduction pathway, This study indicates that OSM may play a key role in promoting TF expression in SMCs within atherosclerotic lesion s. (C) 2001 by The American Society of Hematology.