Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines.
To test the hypothesis that nitric oxide (NO) limits endothelial activation, we treated cytokine-stimulated human saphenous vein endothelial cells with several NO donors and assessed their effects on the inducible expression of vascular cell adhesion molecule-1 (VCAM-1). In a concentration-dependent manner, NO inhibited interleukin (IL)-1 alpha-stimulated VCAM-1 expression by 35-55% as determined by cell surface enzyme immunoassays and flow cytometry. This inhibition was paralleled by reduced monocyte adhesion to endothelial monolayers in nonstatic assays, was unaffected by cGMP analogues, and was quantitatively similar after stimulation by either IL-1 alpha, IL-1 beta, IL-4, tumor necrosis factor (TNF alpha), or bacterial lipopolysaccharide. NO also decreased the endothelial expression of other leukocyte adhesion molecules (E-selectin and to a lesser extent, intercellular adhesion molecule-1) and secretable cytokines (IL-6 and IL-8). Inhibition of endogenous NO production by L-N-monomethyl-arginine also induced the expression of VCAM-1, but did not augment cytokine-induced VCAM-1 expression. Nuclear run-on assays, transfection studies using various VCAM-1 promoter reporter gene constructs, and electrophoretic mobility shift assays indicated that NO represses VCAM-1 gene transcription, in part, by inhibiting NF-kappa B. We propose that NO's ability to limit endothelial activation and inhibit monocyte adhesion may contribute to some of its antiatherogenic and antiinflammatory properties within the vessel wall.
De Caterina
R
R
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Libby
P
P
Peng
H B
HB
Thannickal
V J
VJ
Rajavashisth
T B
TB
Gimbrone
M A
MA
Shin
W S
WS
Liao
J K
JK
D001483:Base Sequence; D015815:Cell Adhesion Molecules / Q000096:biosynthesis* / Q000235:genetics; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000378:metabolism*; D005978:Glutathione / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D008969:Molecular Sequence Data; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000502:physiology*; D009599:Nitroprusside / Q000494:pharmacology; D009603:Nitroso Compounds / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D026422:S-Nitrosoglutathione; D019010:Vascular Cell Adhesion Molecule-1
D015815:Cell Adhesion Molecules; D016207:Cytokines; D016328:NF-kappa B; D009603:Nitroso Compounds; D012333:RNA, Messenger; D019010:Vascular Cell Adhesion Molecule-1; D009599:Nitroprusside; D009569:Nitric Oxide; D026422:S-Nitrosoglutathione; C002385:linsidomine; D008981:Molsidomine; D005978:Glutathione