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.
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 humanCD14+ derived DC, indicates a role of IMPDH and a dependency on the de novo purine synthesis pathway.
Authors: Sebastian Eickenberg; Eva Mickholz; Elisabeth Jung; Jerzy-Roch Nofer; Hermann J Pavenstadt; Annett M Jacobi Journal: Arthritis Res Ther Date: 2012 Impact factor: 5.156