αB-crystallin/HspB5 regulates endothelial-leukocyte interactions by enhancing NF-κB-induced up-regulation of adhesion molecules ICAM-1, VCAM-1 and E-selectin.
αB-crystallin is a small heat shock protein, which has pro-angiogenic properties by increasing survival of endothelial cells and secretion of vascular endothelial growth factor A. Here we demonstrate an additional role of αB-crystallin in regulating vascular function, through enhancing tumor necrosis factor α (TNF-α) induced expression of endothelial adhesion molecules involved in leukocyte recruitment. Ectopic expression of αB-crystallin in endothelial cells increases the level of E-selectin expression in response to TNF-α, and enhances leukocyte-endothelial interaction in vitro. Conversely, TNF-α-induced expression of intercellular adhesion molecule 1, vascular cell adhesion molecule 1 and E-selectin is markedly inhibited in endothelial cells isolated from αB-crystallin-deficient mice. This is associated with elevated levels of IκB in αB-crystallin deficient cells and incomplete degradation upon TNF-α stimulation. Consistent with this, endothelial adhesion molecule expression is reduced in inflamed vessels of αB-crystallin deficient mice, and leukocyte rolling velocity is increased. Our data identify αB-crystallin as a new regulator of leukocyte recruitment, by enhancing pro-inflammatory nuclear factor κ B-signaling and endothelial adhesion molecule expression during endothelial activation.
The Rudbeck Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, 751 85, Uppsala, Sweden.
Lothar C
LC
Dieterich
Hua
H
Huang
Sara
S
Massena
Nikola
N
Golenhofen
Mia
M
Phillipson
Anna
A
Dimberg
D021581:Active Transport, Cell Nucleus; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000096:biosynthesis* / Q000235:genetics; D002460:Cell Line; D042783:Endothelial Cells / Q000166:cytology*; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000096:biosynthesis / Q000235:genetics; D007249:Inflammation; D019169:Jurkat Cells; D036904:Leukocyte Rolling / Q000502:physiology*; D007962:Leukocytes / Q000166:cytology*; D008297:Male; D051379:Mice; D055806:Microvessels / Q000166:cytology; D016328:NF-kappa B / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D015854:Up-Regulation; D038203:alpha-Crystallin B Chain / Q000235:genetics / Q000502:physiology*; D038201:alpha-Crystallins / Q000172:deficiency* / Q000235:genetics
C059215:CRYAB protein, human; D015815:Cell Adhesion Molecules; C525420:Cryab protein, mouse; D020672:I-kappa B Proteins; D016328:NF-kappa B; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D038203:alpha-Crystallin B Chain; D038201:alpha-Crystallins