Hyperosmotic stimuli inhibit VCAM-1 expression in cultured endothelial cells via effects on interferon regulatory factor-1 expression and activity.

Abstract:

:Transcriptional up-regulation of the VCAM-1 gene, induced by proinflammatory cytokines such as IL-1beta and TNF-alpha, requires activation of not only NF-kappaB, but also involves interferon regulatory factor (IRF)-1. During a study of gene induction by mechanical stimuli in cultured human endothelial cells, we noted that medium hyperosmolarity appeared to influence cytokine-induced expression of VCAM-1. Indeed, addition of hyperosmotic, pathophysiologically relevant concentrations of NaCl effectively inhibited IL-1beta or TNF-alpha induction of VCAM-1, but not E-selectin, at the level of mRNA and cell surface protein. Because induction of both VCAM-1 and E-selectin by these cytokines is NF-kappaB dependent, we investigated whether the inhibitory effect of hyperosmotic medium might involve IRF-1. Electrophoretic mobility shift assays of the VCAM-1 promoter demonstrated that hyperosmotic medium suppressed IL-1beta- or TNF-alpha-activated binding activities of IRF-1, but not NF-kappaB, to their respective sites. Hyperosmotic medium also inhibited the expression of IRF-1 induced by TNF-alpha or IFN-gamma. Furthermore, hyperosmotic medium inhibited TNF-alpha or IFN-gamma induction of guanylate binding protein-1, another IRF-1-dependent gene. Taken together, hyperosmolarity selectively inhibits cytokine-induced VCAM-1 in endothelial cells, via an IRF-1-dependent mechanism. Thus, pathophysiological fluctuations in plasma osmolarity may influence certain endothelial-dependent components of the inflammatory response and host defense mechanisms.

journal_name

Eur J Immunol

authors

Ochi H,Masuda J,Gimbrone MA

doi

10.1002/1521-4141(200207)32:7<1821::AID-IMMU1821>3

keywords:

subject

Has Abstract

pub_date

2002-07-01 00:00:00

pages

1821-31

issue

7

eissn

0014-2980

issn

1521-4141

journal_volume

32

pub_type

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