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J. Biol. Chem., Vol. 278, Issue 27, 24888-24895, July 4, 2003

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Adherent Leukocytes Prevent Adenosine Formation and Impair Endothelial Barrier Function by Ecto-5'-nucleotidase/CD73-dependent Mechanism^*

Tiina Henttinen, Sirpa Jalkanen and Gennady G. Yegutkin 

From the MediCity Laboratory and Department of Medical Microbiology, Turku University and National Public Health Institute, FIN-20520 Turku, Finland

Extracellular purines are important signaling molecules that mediate both inflammatory (ATP, ADP) and anti-inflammatory (adenosine) effects in the vasculature. The duration and magnitude of purinergic signaling is governed by a network of purine-converting ectoenzymes, and endothelial and lymphoid cells are generally characterized by counteracting ATP-inactivating and ATP-regenerating/adenosine-eliminating, phenotypes, respectively. By using cultured human umbilical vein endothelial cells and normal or leukemic lymphocytes as an in vitro model of leukocyte-endothelial interactions, we have identified a link between the adhesion cascade and extracellular purine turnover. Upon adhesion, lymphocytes suppress endothelial purine metabolism via (i) inhibition of ecto-5'-nucleotidase/CD73-mediated AMP hydrolysis, (ii) rapid deamination of the remaining adenosine, and (iii) maintenance of the sustained pericellular ATP level through continuous nucleotide release and phosphotransfer reactions. Compensation of the loss of adenosine promotes vascular barrier function (measured as a paracellular flux of 70 kDa fluorescein isothiocyanate-dextran) and decreases transendothelial leukocyte migration. Together, these data show that adherent lymphocytes attempt to prevent adenosine formation in the endothelial environment that, as a consequence, may impair the vascular barrier function and facilitate the subsequent step of leukocyte transmigration into the tissue. These leukocyte adhesion-mediated shifts in the local nucleotide and nucleoside concentrations represent a previously unrecognized paracrine mechanism affecting the functional state of the targeted vascular endothelium and coordinately regulating lymphocyte trafficking between the blood and tissues.

Received for publication, January 23, 2003 , and in revised form, April 2, 2003.

^* This work was supported by the Finnish Academy and the Sigrid Juselius Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: MediCity, Tykistökatu 6A, 20520 Turku, Finland. E-mail: genyeg{at}utu.fi.

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