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Blood, 15 June 2006, Vol. 107, No. 12, pp. 4938-4945. Prepublished online as a Blood First Edition Paper on March 2, 2006; DOI 10.1182/blood-2005-09-3803.
Submitted September 22, 2005
MRC Centre for Inflammation Research, Queen's Medical Research Institute, Edinburgh, United Kingdom * Corresponding author; email: i.dransfield{at}ed.ac.uk.
The selectin family of molecules (L-, P- and E-selectin) mediates adhesive interactions between leukocytes and endothelial cells required for recruitment of leukocytes to inflammatory sites. Soluble E-selectin levels are elevated in inflammatory diseases and act to promote neutrophil
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| Copyright © 2006 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
2 integrin-mediated adhesion by prolonging Ca2+ mobilization. Although soluble E-selectin alone was unable to initiate Ca2+ signaling, it allowed a novel permissive SOCE following the initial PAF-induced release of Ca2+ from IP3-sensitive stores. This induction of permissive SOCE in response to soluble E-selectin and PAF was shown to act through a GPCR coupled to PTX-insensitive Gq/11. Furthermore, we demonstrated that permissive SOCE was mediated by TRPC due to its sensitivity to specific inhibition by MRS1845 and Gd3+ and that TRPC6 was the principal TRPC family member expressed by human neutrophils. In terms of mechanism, we demonstrated that soluble E-selectin activated Src family tyrosine kinases, an effect that was upstream of PI 3-kinase in a signaling pathway that regulates permissive SOCE following exposure of neutrophils to PAF. In summary, this report provides the first evidence for communication between an inflammatory mediator and adhesion receptor(s) at a molecular level, through selectin receptor ligation allowing permissive SOCE to occur following PAF stimulation of human neutrophils.
