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B
activation in immunostimulated endothelial cells
Department of Surgery, University of Medicine and Dentistry-New Jersey Medical School, Newark, New Jersey 07103
Na+/H+
exchanger (NHE) activation has been documented to contribute to
endothelial cell injury caused by inflammatory states. However, the
role of NHEs in regulation of the endothelial cell inflammatory
response has not been investigated. The present study tested the
hypothesis that NHEs contribute to endothelial cell inflammation
induced by endotoxin or interleukin (IL)-1
. NHE inhibition using
amiloride, 5-(N-ethyl-N-isopropyl)-amiloride, and
5-(N-methyl-N-isobutyl)amiloride as well as the
non-amiloride NHE inhibitors cimetidine, clonidine, and harmaline
suppressed endotoxin-induced IL-8 and monocyte chemoattractant protein
(MCP)-1 production by human umbilical endothelial vein cells (HUVECs). The suppressive effect of amiloride on endotoxin-induced IL-8 production was associated with a decreased accumulation of IL-8 mRNA.
NHE inhibitors suppressed both inhibitory (I)
B degradation and
nuclear factor (NF)-
B DNA binding, suggesting that a decrease in
activation of the I
B-NF-
B system contributed to the suppression of HUVEC inflammatory response by NHE blockade. NHE inhibition decreased also the IL-1
-induced HUVEC inflammatory response, because
amiloride suppressed IL-1
-induced E-selectin expression on HUVECs.
These results demonstrate that maximal activation of the HUVEC
inflammatory response requires a functional NHE.
Na+/H+ exchanger; transcription factors; inflammation; cytokines; sepsis; adhesion molecule
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