Receptor activator of nuclear factor kappaB ligand is a novel inducer of tissue factor in macrophages.
BACKGROUND
Although recent studies have suggested a role for the receptor activator of nuclear factor κB ligand (RANKL) in the late stages of atherosclerosis (eg, plaque destabilization and rupture), the underlying mechanisms and subsequent events are unclear.


OBJECTIVE
Because blood clotting is common after plaque rupture, we hypothesized that RANKL influenced tissue factor (TF) expression and activity to initiate the coagulation cascade.


RESULTS
RANKL increased the TF mRNA level and procoagulant activity in macrophages, as determined by semiquantitative reverse transcription polymerase chain reaction (semiquantitative RT-PCR) and a chromogenic assay. TF promoter analysis revealed that AP-1 and Egr-1 are responsible for RANKL-induced TF transcription. In addition, RANKL increased phosphorylation of c-Jun NH(2)-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK)1/2. RANKL-induced TF expression was attenuated by JNK- and MEK1-specific inhibitors and by small interfering RNA knockdown of c-Jun and Egr-1.


CONCLUSIONS
Our results indicate that RANKL induces TF in macrophages mainly through the cooperative action of AP-1 and Egr-1 via JNK and ERK1/2 pathways. These findings provide strong mechanistic support for the role of RANKL in the thrombogenicity of atherosclerotic plaques.
Kim
Jihye
J
Department of Biochemistry, Yonsei University, Seoul, Korea.
Min
Jeong-Ki
JK
Park
Jeong Ae
JA
Doh
Hyun-Ju
HJ
Choi
Yeon-Sook
YS
Rho
Jaerang
J
Kim
Young-Myeong
YM
Kwon
Young-Guen
YG
D000818:Animals; D050197:Atherosclerosis / Q000453:epidemiology / Q000378:metabolism / Q000503:physiopathology*; D002460:Cell Line; D004277:DNA, Single-Stranded / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D010766:Phosphorylation / Q000502:physiology; D053245:RANK Ligand / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012307:Risk Factors; D013925:Thromboplastin / Q000235:genetics* / Q000378:metabolism; D013927:Thrombosis / Q000453:epidemiology / Q000378:metabolism / Q000503:physiopathology*; D014158:Transcription, Genetic / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
C400152:DNA enzyme ED5; D004277:DNA, Single-Stranded; D053245:RANK Ligand; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C505689:Tnfsf11 protein, mouse; D013925:Thromboplastin; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases