Unconjugated Bilirubin Inhibits VCAM-1-Mediated Transendothelial Leukocyte Migration

During lymphocyte migration, engagement of VCAM-1 stimulates the generation of endothelial cell-derived reactive oxygen species (ROS) and activation of matrix metalloproteinases, facilitating endothelial retraction. Because bilirubin is a potent antioxidant, we examined the hypothesis that this bile...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2005-03, Vol.174 (6), p.3709-3718
Main Authors: Keshavan, Pavitra, Deem, Tracy L, Schwemberger, Sandy J, Babcock, George F, Cook-Mills, Joan M, Zucker, Stephen D
Format: Article
Language:English
Subjects:
Animals
Asthma - drug therapy
Asthma - immunology
Asthma - pathology
Bilirubin - pharmacology
Cell Line
Cell Movement - drug effects
Cell Movement - physiology
Endothelium, Vascular - cytology
Endothelium, Vascular - drug effects
Endothelium, Vascular - immunology
Eosinophilia - drug therapy
Eosinophilia - immunology
Eosinophilia - pathology
Female
Leukocytes - drug effects
Leukocytes - physiology
Lung - drug effects
Lung - immunology
Lung - pathology
Mice
Mice, Inbred C57BL
Ovalbumin - immunology
Signal Transduction - drug effects
Vascular Cell Adhesion Molecule-1 - physiology
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Summary:During lymphocyte migration, engagement of VCAM-1 stimulates the generation of endothelial cell-derived reactive oxygen species (ROS) and activation of matrix metalloproteinases, facilitating endothelial retraction. Because bilirubin is a potent antioxidant, we examined the hypothesis that this bile pigment inhibits VCAM-1-dependent cellular events. The migration of isolated murine splenic lymphocytes across monolayers of murine endothelial cell lines (which constitutively express VCAM-1) is significantly inhibited by physiological concentrations of bilirubin, in the absence of an effect on lymphocyte adhesion. Bilirubin administration also suppresses VCAM-1-stimulated ROS generation and reduces endothelial cell matrix metalloproteinase activity. In a murine asthma model characterized by VCAM-1-dependent airway inflammation, treatment of C57BL6/J mice with i.p. bilirubin decreases the total leukocyte count in the lung parenchyma and lavage fluid, through specific inhibition of eosinophil and lymphocyte infiltration. Blood eosinophil counts were increased in bilirubin-treated animals, while VCAM-1 expression in the capillary endothelium and cytokine levels in both lung lavage and supernatants from cultured lymph node lymphocytes were unchanged, suggesting that bilirubin inhibits leukocyte migration. bilirubin blocks VCAM-1-dependent lymphocyte migration in vitro and ameliorates VCAM-1-mediated airway inflammation in vivo, apparently through the suppression of cellular ROS production. These findings support a potential role for bilirubin as an endogenous immunomodulatory agent.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.174.6.3709