Inosine 5'-monophosphate dehydrogenase inhibition by mycophenolic acid impairs maturation and function of dendritic cells.
BACKGROUND
The mechanism of action of mycophenolic acid (MPA) has been described as a blockade of inosine 5'-monophosphate dehydrogenase (IMPDH) and is thought to selectively influence T- and B-lymphocytes due to their strong dependency on guanine nucleotides synthesized via the de novo purine synthesis pathway. Recent evidence suggests MPA to affect antigen-presenting cells.


METHODS
Using CD14+ derived human dendritic cells (DC) we have investigated the effects of MPA on differentiation, maturation and function and studied intracellular nucleotide content and IMPDH activity.


RESULTS
GTP content and IMPDH activities of DC were strongly and dose-dependently decreased when MPA was present during the entire culture period or was added after the fifth (immature DC) or the seventh (mature DC) day of culture. Concurrent to low GTP levels, a dose-dependent reduction in the expression of CD80, CD86, CD40, CD54 and CD83 was seen which was accompanied by a decreased capacity of DC to stimulate T-cells. Our data for the first time shows a direct effect of MPA on the maturation and function of human CD14+ derived DC, indicates a role of IMPDH and a dependency on the de novo purine synthesis pathway.
Dubsky
Peter C
PC
Vienna Medical School, Department of Surgery, A-1090 Wien, Währinger Gürtel 18-20, Austria. peter.dubsky@meduniwien.ac.at
Friedl
Josef
J
Stift
Anton
A
Bachleitner-Hofmann
Thomas
T
Jakesz
Raimund
R
Gnant
Michael F X
MF
Weigel
Guenter
G
D000255:Adenosine Triphosphate / Q000378:metabolism; D015703:Antigens, CD / Q000032:analysis; D015415:Biomarkers / Q000032:analysis; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016130:Immunophenotyping; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D009173:Mycophenolic Acid / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology
D015703:Antigens, CD; D015415:Biomarkers; D004791:Enzyme Inhibitors; D006160:Guanosine Triphosphate; D000255:Adenosine Triphosphate; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid