Molecular action of methotrexate in inflammatory diseases

Abstract

Despite the recent introduction of biological response modifiers and potent new small-molecule antirheumatic drugs, the efficacy of methotrexate is nearly unsurpassed in the treatment of inflammatory arthritis. Although methotrexate was first introduced as an antiproliferative agent that inhibits the synthesis of purines and pyrimidines for the therapy of malignancies, it is now clear that many of the anti-inflammatory effects of methotrexate are mediated by adenosine. This nucleoside, acting at one or more of its receptors, is a potent endogenous anti-inflammatory mediator. In confirmation of this mechanism of action, recent studies in both animals and patients suggest that adenosine-receptor antagonists, among which is caffeine, reverse or prevent the anti-inflammatory effects of methotrexate.

Figure 1

Methotrexate-induced metabolic changes lead to increased extra-cellular adenosine. ADA = adenosine deaminase; AICAR = aminoimidazolecarboxamidoribonucleotide; AICAside = aminoimidazolecarboxamidoribonucleoside; AK = adenosine kinase; AMPDA = AMP deaminase; DHF = dihydrofolate; DHF_glu = dihydrofolate polyglutamate; ecto-5'NT = ecto-5'nucleotidase; FAICAR = formyl-AICAR; IMP = inosine monophosphate; MTX = methotrexate; MTX_glu = methotrexate polyglutamate; RFC1 = reduced folate carrier 1.