Verotoxin-1 stimulation of macrophage-like THP-1 cells up-regulates tissue factor expression through activation of c-Yes tyrosine kinase: Possible signal transduction in tissue factor up-regulation.
Verotoxin (VT)-producing Escherichia coli (E. coli) O157:H7 infections are frequently complicated by thrombotic angiopathy, hemolytic uremic syndrome (HUS) and neurological symptoms. The present data demonstrate that VT-1 (Shiga toxin) stimulation of macrophage-like THP-1 cells up-regulates the activity, antigen and mRNA levels of tissue factor (TF), a key cofactor of the coagulation-inflammation-thrombosis circuit. This up-regulation is accompanied by phosphorylation of phosphatidylinositol 3-kinase (PI3-kinase), IkappaB kinase beta (IKKbeta) and extracellular signal-regulated kinase 2 (ERK2). Changes in TF mRNA levels were in parallel with the activation of NF-kappaB/Rel and Egr-1 activation, but not with AP-1. Inhibition of PI3-kinase attenuated VT-1-induced phosphorylation of IKKbeta and ERK2, and the up-regulation of TF mRNA levels. VT-1 stimulation rapidly activated c-Yes tyrosine kinase, a member of the Src family. Treatment of the cells with c-Yes antisense oligos attenuated the VT-1-induced phosphorylation of PI3-kinase, IKKbeta and ERK2, activations of NF-kappaB/Rel and Egr-1, and up-regulation of TF mRNA levels. These results suggest that VT-1-induced macrophage stimulation activates c-Yes, which then up-regulates TF expression through activation of the IKKbeta/proteasome/NF-kappaB/Rel and MEK/ERK2/Egr-1 pathways via activation of PI3-kinase. Induction of macrophage TF expression by VT-1 may play an important role in the acceleration of the coagulation-inflammation-thrombosis circuit during infections by VT-producing E. coli.
Murata
Kazuya
K
Department of Molecular and Cellular Pathophysiology, Showa Pharmaceutical University, Higashi Tamagawa Gakuen, Machida, Tokyo 194-8543, Japan.
Higuchi
Toshiyuki
T
Takada
Kimihiko
K
Oida
Koji
K
Horie
Shuichi
S
Ishii
Hidemi
H
D002454:Cell Differentiation; D045744:Cell Line, Tumor; D006801:Humans; D007948:Leukemia, Monocytic, Acute; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051575:Proto-Oncogene Proteins c-yes / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D022622:Shiga Toxin 1 / Q000494:pharmacology*; D015398:Signal Transduction; D013925:Thromboplastin / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation
D012333:RNA, Messenger; D022622:Shiga Toxin 1; D014157:Transcription Factors; D013925:Thromboplastin; D051575:Proto-Oncogene Proteins c-yes