Folinic acid antagonizes methotrexate-induced differentiation of monocyte progenitors.
OBJECTIVE
The anti-inflammatory action of low-dose methoxetrate (MTX) in the treatment of rheumatoid arthritis (RA) appears to be partially impaired by folate supplementation. Here we investigated whether a folate excess impairs monocyte differentiation, a putative anti-inflammatory action of low-dose MTX.


METHODS
Monocyte differentiation of U937 promonocytic cells was assessed by CD11b and CD14 immunostaining and fluorescent absorbent cell sorting (FACS) analysis. Cell proliferation and viability were determined by cell counts and trypan-blue staining, respectively. Nuclear apoptosis was assessed by 7-actinomycin staining. Cells were treated with 10(-10)-10(-6) M MTX in the presence or absence of folinic acid. Exposure to 1,25-OH-vitamine D(3) and TGF-beta served as a positive control of monocyte differentiation in U937 cells.


RESULTS
Low-dose MTX-induced monocyte differentiation was marginal when compared with 1,25-OH-D(3) + TGF-beta treatment. Low-dose MTX inhibited cell proliferation, induced apoptosis, and reduced cell viability. All the antiproliferative, cytotoxic, and monocyte differentiating effects of MTX were completely reversed by folinic acid.


CONCLUSIONS
Monocyte differentiation is part of the folate-dependent MTX actions.
Möller
Burkhard
B
Medizinische Klinik III, Klinikum der Johann Wolfgang, Goethe-Universität, Theodor-Stern-Kai 7, 60590 Frankfurt/M., Germany. B.Moeller@em.uni-frankfurt.de
Kukoc-Zivojnov
Natasa
N
Okamgba
Stella
S
Kessler
Uta
U
Puccetti
Elena
E
Ottmann
Oliver G
OG
Kaltwasser
Joachim P
JP
Hoelzer
Dieter
D
Ruthardt
Martin
M
D018501:Antirheumatic Agents / Q000494:pharmacology*; D017209:Apoptosis; D018845:CD11 Antigens / Q000378:metabolism; D002117:Calcitriol / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D005434:Flow Cytometry; D006801:Humans; D002955:Leucovorin / Q000494:pharmacology*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008727:Methotrexate / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured
D018501:Antirheumatic Agents; D018845:CD11 Antigens; D018950:Lipopolysaccharide Receptors; D002117:Calcitriol; D002955:Leucovorin; D008727:Methotrexate