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IFN- Induced Adenosine Production on the Endothelium: A Mechanism Mediated by CD73 (Ecto-5'-Nucleotidase) Up-Regulation¹

Jussi Niemelä^*, Tiina Henttinen^*, Gennady G. Yegutkin^*, Laura Airas^*, Anna-Maija Kujari^*, Pertti Rajala and Sirpa Jalkanen^2,*

^* MediCity Research Laboratory and Department of Medical Microbiology, Turku University, Turku and National Public Health Institute, Turku, Finland; and Department of Surgery, Turku University Central Hospital, Turku, Finland

CD73 (ecto-5'-nucleotidase; EC 3.1.3.5) participates in lymphocyte binding to endothelial cells and converts extracellular AMP into a potent anti-inflammatory substance adenosine. However, the regulation of expression and function of CD73 has remained largely unknown. In this study, we show that IFN- produces a time- and dose-dependent long-term up-regulation of CD73 on endothelial cells, but not on lymphocytes both at protein and RNA levels. Moreover, CD73-mediated production of adenosine is increased after IFN- treatment on endothelial cells, resulting in a decrease in the permeability of these cells. Subsequent to induction with PMA, FMLP, dibutyryl cAMP, thrombin, histamine, IL-1, TNF-, and LPS, no marked changes in the level of CD73 expression on endothelial cells are observed. We also show that CD73 is up-regulated in vivo on the vasculature after intravesical treatment of urinary bladder cancers with IFN-. In conclusion, distinct behavior of lymphocyte and endothelial CD73 subsequent to cytokine treatment further emphasizes the existence of cell type-specific mechanisms in the regulation of CD73 expression and function. Overall, these results suggest that IFN- is a relevant in vivo regulator of CD73 in the endothelial-leukocyte microenvironment in infections/inflammations, and thus has a fundamental role in controlling the extent of inflammation via CD73-dependent adenosine production.

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