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Published online before print October 2, 2003

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(Journal of Leukocyte Biology. 2004;75:127-134.)
© 2004 by Society for Leukocyte Biology

Activation of A_2A adenosine receptors inhibits expression of 4/ß1 integrin (very late antigen-4) on stimulated human neutrophils

Gail W. Sullivan^*,1, David D. Lee, William G. Ross^*, Jeffrey A. DiVietro, Courtney M. Lappas, Michael B. Lawrence and Joel Linden^*

Departments of
^* Internal Medicine,
Biomedical Engineering, and
Pharmacology, University of Virginia, Charlottesville

¹Correspondence: Cardiovascular Research Center, MR-5 Room 1314, 415 Lane Rd. (Box 801394), University of Virginia Health Sciences Center, Charlottesville, VA 22908. E-mail: gws3u{at}virginia.edu

The 4/ß1 integrin very late antigen-4 (CD49d/CD29) is up-regulated on circulating neutrophils of septic patients. Although no individual agent mimics this effect of sepsis, we now report that following priming of human neutrophils with lipopolysaccharide or tumor necrosis factor (TNF-), addition of formyl-Met-Leu-Phe (fMLP) results in a "stimulated", sepsis-like, four- to fivefold rise in CD49d expression. TNF/fMLP stimulation also produced a similar increase in CD49d-mediated adhesion of neutrophils to a vascular cell adhesion molecule-1 (VCAM-1)-coated surface. Adenosine is a naturally occurring, anti-inflammatory mediator released from injured or inflamed tissues. We observed that stimulated neutrophil CD49d expression was decreased by activation of A_2A adenosine receptors (A_2AAR) with the selective agonist 4-{3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-cyclohexanecarboxylicacid methyl ester (ATL146e; EC₅₀=6.4 nM). ATL146e (100 nM) also reduced the fraction of stimulated neutrophils that adhered to VCAM-1 from 38 ± 6% to 27 ± 5%. Inhibition of CD49d expression was equally inhibited by ATL146e, added before or after TNF priming, and was reversed by incubation with the A_2AAR-selective antagonist 4-{2-[7-amino-2-(2-furyl) (1, 2, 4)triazolo(2,3-a) (1, 3, 5)triazin-5-yl-amino]ethyl}-phenol (ZM241385; 100 nM). A suboptimal ATL146e concentration (1 nM) combined with the type IV phosphodiesterase inhibitor rolipram (100 nM) synergistically decreased stimulated CD49d expression by >50%. The cyclic adenosine monophosphate (cAMP)-dependent kinase [protein kinase A (PKA)] inhibitor H-89 (10 µM) reversed the effect of ATL146e on stimulated CD49d expression. Other means of increasing cAMP in neutrophils also decreased stimulated CD49d expression. We conclude that adenosine binding to A_2AAR counteracts stimulation of neutrophil CD49d integrin expression and neutrophil binding to VCAM-1 via a cAMP/PKA-mediated pathway.

Key Words: inflammation • adhesion molecules • tumor necrosis factor • lipopolysaccharide • cytokines

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