IFN-beta regulates CD73 and adenosine expression at the blood-brain barrier.
IFN-beta treatment reduces the relapse rate in MS but its mechanism of action remains incompletely understood. Our aim was to clarify the beneficial effect of IFN-beta in the treatment of MS. We assessed the influence of IFN-beta treatment on (i) CD73 expression on the surface of primary cultures of human blood-brain barrier endothelial cells (BBB-EC) and human astrocytes using immunofluorescence staining and flow cytometry, (ii) transmigration of CD4+ T lymphocytes using an in vitro model of BBB and (iii) CD73 enzyme activity, i.e. ecto-5'-nucleotidase activity in the serum of MS patients using a radiochemical assay. IFN-beta increases the expression of ecto-5'-nucleotidase both on BBB-EC and astrocytes. As a consequence, lymphocyte transmigration through BBB-EC is reduced. Importantly, this reduction can be reversed using alpha,beta-methyleneadenosine-5'-diphosphate, a specific inhibitor of ecto-5'-nucleotidase. CD73 is strongly expressed in microvasculature in samples of postmortem MS brain and, moreover, in the majority of MS patients there was a clear upregulation both in the soluble serum ecto-5'-nucleotidase activity and skin microvascular CD73 expression after IFN-beta treatment. Upregulation of ecto-5'-nucleotidase and a subsequent increase in adenosine production might contribute to the beneficial effects of IFN-beta on MS via enhancing the endothelial barrier function.
Niemelä
Jussi
J
Department of Medical Microbiology, MediCity Research Laboratory, University of Turku, Turku, Finland.
Ifergan
Igal
I
Yegutkin
Gennady G
GG
Jalkanen
Sirpa
S
Prat
Alexander
A
Airas
Laura
L
D015720:5'-Nucleotidase / Q000097:blood / Q000378:metabolism*; D000241:Adenosine / Q000378:metabolism*; D000328:Adult; D001253:Astrocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000276:immunology / Q000378:metabolism*; D001921:Brain / Q000098:blood supply; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000276:immunology; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D007370:Interferon Type I / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D011994:Recombinant Proteins; D055815:Young Adult
D007155:Immunologic Factors; D007370:Interferon Type I; D011994:Recombinant Proteins; D015720:5'-Nucleotidase; D000241:Adenosine