title: Inosine 5'-monophosphate dehydrogenase inhibition by mycophenolic acid impairs maturation and function of dendritic cells.
abstract: 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.
authors.affiliation: Vienna Medical School, Department of Surgery, A-1090 Wien, Währinger Gürtel 18-20, Austria. peter.dubsky@meduniwien.ac.at
authors.forename: Peter C
authors.initials: PC
authors.lastname: Dubsky
authors.forename: Josef
authors.initials: J
authors.lastname: Friedl
authors.forename: Anton
authors.initials: A
authors.lastname: Stift
authors.forename: Thomas
authors.initials: T
authors.lastname: Bachleitner-Hofmann
authors.forename: Raimund
authors.initials: R
authors.lastname: Jakesz
authors.forename: Michael F X
authors.initials: MF
authors.lastname: Gnant
authors.forename: Guenter
authors.initials: G
authors.lastname: Weigel
mesh_terms: 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
chemical_list: D015703:Antigens, CD; D015415:Biomarkers; D004791:Enzyme Inhibitors; D006160:Guanosine Triphosphate; D000255:Adenosine Triphosphate; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid