Table 2.

Various mechanisms of low-dose methotrexate dampening the inflammatory response [37^▪]

1. Inhibition of purine and pyrimidine synthesis

2. Promotion of adenosine release with adenosine-mediated suppression of inflammation and of high-mobility group box chromosomal protein 1 (HMGB1) thus inhibiting Toll-like receptor (TLR) activation

3. Suppression of transmethylation reactions and polyamine accumulation

4. Reduced production of matrix metalloproteinases (MMPs), which play a role in tissue remodelling. Reduced synthesis of the inflammatory mediator prostaglandin E2 (PGE2) and of cytokine expression

5. Suppression of the activation of the transduction pathways Janus kinase/signal transducers and activators of transcription (JAK/STAT) and nuclear factor-κB (NF-κB); hence inhibition of the upregulation of multiple pro-inflammatory cytokines