Phenyl methimazole inhibits TNF-alpha-induced VCAM-1 expression in an IFN regulatory factor-1-dependent manner and reduces monocytic cell adhesion to endothelial cells.
Proinflammatory cytokine (e.g., TNF-alpha)-induced expression of endothelial cell adhesion molecules (ECAMs) on the lumenal surface of the vascular endothelium and a consequent increase in leukocyte adhesion are key aspects of pathological inflammation. A promising therapeutic approach to diminish aberrant leukocyte adhesion is, therefore, to inhibit cytokine-induced ECAM expression at the transcription level. Several studies suggest that methimazole, a compound used clinically to treat autoimmune diseases, such as Graves' disease, may also diminish pathological inflammation by suppressing ECAM expression. In this study we probed the hypothesis that a derivative of methimazole, phenyl methimazole (compound 10), can reduce cytokine-induced ECAM expression and consequent leukocyte adhesion. We found that compound 10 1) dramatically inhibits TNF-alpha-induced VCAM-1 mRNA and protein expression in human aortic endothelial cells (HAEC), has a relatively modest inhibitory effect on TNF-alpha induced E-selectin expression and has no effect on ICAM-1 expression; 2) significantly reduces TNF-alpha-induced monocytic (U937) cell adhesion to HAEC under in vitro flow conditions similar to that present in vivo; 3) inhibits TNF-alpha-induced IFN regulatory factor-1 binding to VCAM-1 promoter; and 4) reduces TNF-alpha-induced IRF-1 expression in HAEC. Combined, the results indicate that phenyl methimazole can reduce TNF-alpha-induced VCAM-1 expression in an IFN regulatory factor-1-dependent manner and that this contributes significantly to reduced monocytic cell adhesion to TNF-alpha-activated HAEC.
Dagia
Nilesh M
NM
Department of Chemical Engineering, College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA.
Harii
Norikazu
N
Meli
Antonella E
AE
Sun
Xiaolu
X
Lewis
Christopher J
CJ
Kohn
Leonard D
LD
Goetz
Douglas J
DJ
D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line / Q000187:drug effects / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D003864:Depression, Chemical; D019040:E-Selectin / Q000096:biosynthesis / Q000235:genetics; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D050856:Interferon Regulatory Factor-1; D008713:Methimazole / Q000031:analogs & derivatives / Q000494:pharmacology*; D009000:Monocytes / Q000166:cytology / Q000187:drug effects*; D016328:NF-kappa B / Q000378:metabolism; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D013871:Thiones / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D020298:U937 Cells / Q000187:drug effects / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis* / Q000235:genetics
D004268:DNA-Binding Proteins; D019040:E-Selectin; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D016328:NF-kappa B; D010750:Phosphoproteins; D012333:RNA, Messenger; D013871:Thiones; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; C489637:phenyl methimazole; D018799:Intercellular Adhesion Molecule-1; D008713:Methimazole