Hypoxia enhances induction of endothelial ICAM-1: role for metabolic acidosis and proteasomes.
Intercellular adhesion molecule 1 (ICAM-1) is an important molecule in promotion of polymorphonuclear neutrophil transendothelial migration during inflammation. Coincident with many inflammatory diseases is tissue hypoxia. Thus we hypothesized that combinations of hypoxia and inflammatory stimuli may differentially regulate expression of endothelial ICAM-1. Human endothelial cells were exposed to hypoxia in the presence or absence of added lipopolysaccharide (LPS) and examined for expression of functional ICAM-1. Although hypoxia alone did not induce ICAM-1, the combination of LPS and hypoxia enhanced (3 +/- 0.4-fold over normoxia) ICAM-1 expression. Combinations of hypoxia and LPS significantly increased lymphocyte binding, and such increases were inhibited by addition of anti-ICAM-1 antibodies or antisense oligonucleotides. Hypoxic endothelia showed a > 10-fold increase in sensitivity to inhibitors of proteasome activation, and combinations of hypoxia and LPS enhanced proteasome-dependent cytoplasmic-to-nuclear localization of the nuclear transcription factor-kappa B p65 (Rel A) subunit. Such proteasome activation correlated with hypoxia-evoked decreases in both extracellular and intracellular pH. We conclude from these studies that endothelial hypoxia provides a novel, proteasome-dependent stimulus for ICAM-1 induction.
Zünd
G
G
Department of Anesthesia, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Uezono
S
S
Stahl
G L
GL
Dzus
A L
AL
McGowan
F X
FX
Hickey
P R
PR
Colgan
S P
SP
D000138:Acidosis; D000906:Antibodies / Q000494:pharmacology; D002448:Cell Adhesion; D015687:Cell Hypoxia / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D003593:Cytoplasm / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D015395:Histocompatibility Antigens Class I / Q000502:physiology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis* / Q000276:immunology; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008214:Lymphocytes / Q000166:cytology / Q000502:physiology; D009097:Multienzyme Complexes / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects / Q000502:physiology*
D000906:Antibodies; D015395:Histocompatibility Antigens Class I; D008070:Lipopolysaccharides; D009097:Multienzyme Complexes; D016328:NF-kappa B; D018799:Intercellular Adhesion Molecule-1; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex