NHE blockade inhibits chemokine production and NF-kappaB activation in immunostimulated endothelial cells.
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)-1beta. 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)kappaB degradation and nuclear factor (NF)-kappaB DNA binding, suggesting that a decrease in activation of the IkappaB-NF-kappaB system contributed to the suppression of HUVEC inflammatory response by NHE blockade. NHE inhibition decreased also the IL-1beta-induced HUVEC inflammatory response, because amiloride suppressed IL-1beta-induced E-selectin expression on HUVECs. These results demonstrate that maximal activation of the HUVEC inflammatory response requires a functional NHE.
Németh
Zoltán H
ZH
Department of Surgery, University of Medicine and Dentistry-New Jersey Medical School, Newark, New Jersey 07103, USA.
Deitch
Edwin A
EA
Lu
Qi
Q
Szabó
Csaba
C
Haskó
György
G
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000584:Amiloride / Q000494:pharmacology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors; D018925:Chemokines / Q000096:biosynthesis*; D019040:E-Selectin / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000235:genetics; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors / Q000502:physiology*
D000276:Adjuvants, Immunologic; D018932:Chemokine CCL2; D018925:Chemokines; D019040:E-Selectin; D007375:Interleukin-1; D016209:Interleukin-8; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012333:RNA, Messenger; D017923:Sodium-Hydrogen Exchangers; D000584:Amiloride