Tumor necrosis factor-induced neutrophil adhesion occurs via sphingosine kinase-1-dependent activation of endothelial α₅β₁ integrin
Date
2010
Authors
Sun, W.
Pitson, S.
Bonder, C.
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Journal article
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American Journal of Pathology, 2010; 177(1):436-446
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Wai Y. Sun, Stuart M. Pitson and Claudine S. Bonder
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Abstract
Leukocyte recruitment plays a major role in the immune response to infectious pathogens, as well as during inflammatory and autoimmune disorders. The process of leukocyte extravasation from the blood requires a complex cascade of adhesive events between the leukocytes and the endothelium, including initial leukocyte rolling, adhesion, and finally transendothelial migration. Current research in this area aims to identify the key leukocyte subsets that initiate a given disease and to identify the trafficking molecule(s) that will most specifically inhibit those cells. Herein we demonstrate that tumor necrosis factor (TNF)α activates the integrin α5β1 without altering total expression levels of β1 integrin on human umbilical vein endothelial cells. Moreover, our studies suggest that TNFα-induced β1 activation is dependent on sphingosine kinase-1, but independent of the sphingosine-1-phosphate family of G protein-coupled receptors. We also show, using a parallel plate flow chamber assay, that neutrophil adhesion to TNFα-activated endothelium can be attenuated by blocking α5β1 or its ligand angiopoietin-2. These observations add new complexities that broaden the accepted concept of cellular trafficking with neutrophil adhesion to TNFα activated endothelial cells being sphingosine kinase-1, α5β1, and angiopoietin-2 dependent. Moreover, this work supports the notion that sphingosine kinase-1 may be the single target required for an effective broad spectrum approach to combat inflammation and immune disorders.
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© 2010 American Society for Investigative Pathology