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Rheumatology Advance Access originally published online on May 30, 2003
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Rheumatology 2003; 42: 1189-1196
© 2003 British Society for Rheumatology

Inhibition of cytokine production by methotrexate. Studies in healthy volunteers and patients with rheumatoid arthritis

A. H. Gerards, S. de Lathouder1, E. R. de Groot1, B. A. C. Dijkmans and L. A. Aarden1

Department of Rheumatology, Free University Medical Centre Amsterdam, Amsterdam and 1Department of Immunopathology, Sanquin Research at CLB and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.

Correspondence to: L. A. Aarden, CLB, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands. E-mail: L.Aarden{at}sanquin.nl

Objectives. To analyse whether the beneficial effects of methotrexate in rheumatoid arthritis (RA) could be due to inhibition of inflammatory cytokine production.

Methods. Cytokine production was studied using whole blood (WB) and mononuclear cells (MNC) of healthy volunteers and RA patients. Cultures were stimulated with either bacterial products such as lipo-oligosaccharide (LOS) or Staphylococcus aureus Cowan I (SAC) to activate monocytes or with monoclonal antibodies to CD3 and CD28 to induce polyclonal T-cell activation. We analysed the effect of methotrexate on cytokine production in these systems.

Results. We showed that methotrexate inhibits production of cytokines induced by T-cell activation. Among the cytokines inhibited were interleukin 4 (IL-4), IL-13, IFN{gamma}, tumour necrosis factor-{alpha} (TNF{alpha}) and granulocyte–macrophage colony-stimulating factor. Inhibition was seen at concentrations easily achieved in plasma of RA patients taking the drug. IL-8 production was hardly influenced by methotrexate. Furthermore, inhibition was dependent on the stimulus; IL-6, IL-8, IL-1ß and TNF{alpha} production induced by LOS or SAC was only slightly decreased by methotrexate. The addition of folinic acid or thymidine and hypoxanthine reversed the inhibitory effects of methotrexate on cytokine production. Concentrations of methotrexate required for inhibition varied between donors. Oral intake of 10 mg methotrexate by RA patients led to marked inhibition of cytokine production in blood drawn after 2 h.

Conclusions. Methotrexate turns out to be an efficient inhibitor of cytokine production induced by T-cell activation in freshly drawn blood. This is due to inhibition of the de novo synthesis of purines and pyrimidines. Cytokines produced by monocytes are hardly affected by methotrexate.

KEY WORDS: Methotrexate, Cytokines, Tumour necrosis factor, Rheumatoid arthritis, Whole blood culture


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J. A. M. Wessels, T. W. J. Huizinga, and H.-J. Guchelaar
Recent insights in the pharmacological actions of methotrexate in the treatment of rheumatoid arthritis
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