A novel cell adhesion inhibitor, K-7174, reduces the endothelial VCAM-1 induction by inflammatory cytokines, acting through the regulation of GATA.
A novel inhibitor for the adhesion of monocytes to cytokine-stimulated endothelial cells, K-7174, was selected by an assay system using the cultured human monocytic cells and human endothelial cells. K-7174 inhibited the expression of vascular cell adhesion molecule-1 (VCAM-1) induced by either tumor necrosis factor alpha or interleukin-1beta, without affecting the induction of intercellular adhesion molecule-1 or E-selectin. K-7174 had no effect on the stability of VCAM-1 mRNA. Electrophoretic mobility shift assay revealed that its inhibitory effect on VCAM-1 induction was mediated by an effect on the binding to the GATA motifs in the VCAM-1 gene promoter region. K-7174 did not influence the binding to any of the following binding motifs: octamer binding protein, AP-1, SP-1, ets, NFkappaB, or interferon regulatory factor. These results suggest that the regulation of GATA binding may become a new target for anti-inflammatory drug development, acting through a mechanism independent from NFkappaB activity.
Umetani
M
M
Department of Molecular Biology and Medicine, University of Tokyo, Japan.
Nakao
H
H
Doi
T
T
Iwasaki
A
A
Ohtaka
M
M
Nagoya
T
T
Mataki
C
C
Hamakubo
T
T
Kodama
T
T
D000840:Anisoles / Q000737:chemistry / Q000494:pharmacology*; D001381:Azepines / Q000737:chemistry / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019040:E-Selectin / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D050981:Erythroid-Specific DNA-Binding Factors; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008970:Molecular Weight; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D020298:U937 Cells; D014471:Umbilical Veins; D015854:Up-Regulation / Q000187:drug effects; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics* / Q000378:metabolism
D000840:Anisoles; D001381:Azepines; D004268:DNA-Binding Proteins; D019040:E-Selectin; D050981:Erythroid-Specific DNA-Binding Factors; D007375:Interleukin-1; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; C410337:K 7174; D004247:DNA