Fig. 1

Methotrexate: Cell—specific mechanism of action in Rheumatoid Arthritis. With respect to T cells, methotrexate causes the inhibition of the dihydrofolate reductase (DHFR)-mediated reduction of dihydrobiopterin (BH2) to tetrahydrobiopterin (BH4). This results in nitric oxide synthase (NOS) uncoupling and increased production of reactive oxygen species (ROS). The ROS activate JUN N-terminal kinase (JNK). In turn, the activated JNK induces genes encoding proteins that regulate sensitivity to apoptosis and cell cycle progression. In the case of fibroblast—like synoviocytes, methotrexate causes inhibition of of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase (ATIC). This causes increased release of adenosine and activation of adenosine receptors, resulting in the inhibition of NF-κB with subsequent anti-inflammatory effects [30]