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 coagulation cascade. TF is known to play a major role in mediating thrombosis and thrombotic episodes associated with the progression of atherosclerosis. Macrophages at inflammatory sites, such as atherosclerotic lesions, release numerous cytokines that are capable of modulating TF expression. This study examined the role of oncostatin M (OSM), a macrophage/ T-lymphocyte-restricted cytokine, in the expression of TF in vascular smooth muscle cells (SMCs). It is reported here that OSM stimulated a biphasic and sustained pattern of TF messenger RNA (mRNA). The effect of OSM on TF mRNA expression was regulated at the transcriptional level as determined by nuclear run-offs and transient transfection of a TF promoter-reporter gene construct. OSM-induced TF expression was regulated primarily by the transcription factor NF-kappaB. Activation of NF-kappaB by OSM did not require IkappaB-alpha degradation. Inhibition of MEK activity by U0126 prevented OSM-induced TF expression by suppressing NF-kappaB DNA binding activity as determined by gel-shift analysis. Further, inhibition of Erk-1/2 protein by antisense treatment resulted in suppression of TF mRNA expression, indicating a role for Erk-1/2 in modulating NF-kappaB DNA binding activity. These studies suggest that the induced expression of TF by OSM is primarily through the activation of NF-kappaB and that activation of NF-kappaB is regulated in part by the MEK/Erk-1/2 signal transduction pathway. This study indicates that OSM may play a key role in promoting TF expression in SMCs within atherosclerotic lesions.
Nishibe
T
T
Department of Molecular Biology, The Hope Heart Institute and Providence Medical Center, Seattle, WA, USA.
Parry
G
G
Ishida
A
A
Aziz
S
S
Murray
J
J
Patel
Y
Y
Rahman
S
S
Strand
K
K
Saito
K
K
Saito
Y
Y
Hammond
W P
WP
Savidge
G F
GF
Mackman
N
N
Wijelath
E S
ES
D001777:Blood Coagulation; D002478:Cells, Cultured; D006801:Humans; D007700:Kinetics; D048369:MAP Kinase Kinase 1; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D009130:Muscle, Smooth / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D016376:Oligonucleotides, Antisense; D053683:Oncostatin M; D010455:Peptides / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
D016328:NF-kappa B; C508351:OSM protein, human; D016376:Oligonucleotides, Antisense; D010455:Peptides; D053683:Oncostatin M; D013925:Thromboplastin; D017346:Protein Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases