Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis - PubMed (original) (raw)

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Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis

M Cutolo et al. Ann Rheum Dis. 2001 Aug.

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Figure 1

Figure 1

Adenosine increase by MTX and subsequent immunosuppression through adenosine receptors. (A) MTX inhibits both, conversion of GAR → FGAR and AICAR → FAICAR. However, inhibition of the second step is stronger, which results in accumulation of AICAR. (B) Accumulated AICAR inhibits AMP deaminase and adenosine deaminase (ADA), which increases adenosine-5'-P and adenosine (C). (D) Intracellular accumulation of adenosine-5'-P and adenosine results in an increase of these compounds in the extracellular space. Here, adenosine-5'-P is converted to adenosine, which binds to the specific receptor subtypes A1, A2a, and A2b (E). Probably, there will be a preponderance of the A2 receptor pathway, yielding an increase of cyclic adenosine monophosphate (cAMP) in the cell (F). (G) cAMP increase leads to immunosuppression. AMP = adenosine-5'-monophosphate; MTX = methotrexate.

Figure 2

Figure 2

Anti-inflammatory effects exerted by low dose MTX at the level of the synovial tissue in RA. (A) MTX reduces monocytic cell growth and increases their apoptosis. (B) MTX decreases the IL1 and IL6 secretion and increases IL1ra production. At the same time, MTX increases IL4 and IL10 gene expression and decreases gene expression of proinflammatory Th1 cytokines (IL2 and IFNγ). (C) MTX seems to exert indirect inhibition of COX-2 synthesis and neutrophil chemotaxis. (D) MTX exerts indirect inhibitory effects (through modulation of cytokines) on synovial metalloproteinase (MMP) production and stimulates their inhibitors (TIMP) (E). MTX = methotrexate; IL1ra = interleukin-1 receptor antagonist; IFNγ = interferon γ; COX-2 = cyclo-oxygenase-2; MMP = metalloproteinase; TIMP = tissue inhibitor of metalloproteinase.

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