IFN-alpha induced adenosine production on the endothelium: a mechanism mediated by CD73 (ecto-5'-nucleotidase) up-regulation.
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-alpha 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-alpha 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-1beta, TNF-alpha, 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-alpha. 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-alpha 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.
Niemelä
Jussi
J
MediCity Research Laboratory and Department of Medical Microbiology, Turku University, Turku, Finland.
Henttinen
Tiina
T
Yegutkin
Gennady G
GG
Airas
Laura
L
Kujari
Anna-Maija
AM
Rajala
Pertti
P
Jalkanen
Sirpa
S
D015720:5'-Nucleotidase / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D000241:Adenosine / Q000096:biosynthesis*; D000368:Aged; D002460:Cell Line; D002463:Cell Membrane Permeability / Q000276:immunology; D002478:Cells, Cultured; D004306:Dose-Response Relationship, Immunologic; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D008875:Middle Aged; D018307:Neoplasms, Squamous Cell / Q000098:blood supply / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D012313:RNA / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*; D001743:Urinary Bladder / Q000098:blood supply / Q000201:enzymology / Q000276:immunology; D001749:Urinary Bladder Neoplasms / Q000098:blood supply / Q000201:enzymology / Q000276:immunology / Q000473:pathology
D016898:Interferon-alpha; D012313:RNA; D015720:5'-Nucleotidase; D000241:Adenosine