The antiinflammatory mechanism of methotrexate. Increased adenosine release at inflamed sites diminishes leukocyte accumulation in an in vivo model of inflammation.

Abstract

Methotrexate, a folate antagonist, is a potent antiinflammatory agent when used weekly in low concentrations. We examined the hypothesis that the antiphlogistic effects of methotrexate result from its capacity to promote intracellular accumulation of 5-aminoimidazole4-carboxamide ribonucleotide (AICAR) that, under conditions of cell injury, increases local adenosine release. We now present the first evidence to establish this mechanism of action in an in vivo model of inflammation, the murine air pouch model. Mice were injected intraperitoneally with either methotrexate or saline for 34 wk during induction of air pouches. Pharmacologically relevant doses of methotrexate increased splenocyte AICAR content, raised adenosine concentrations in exudates from carrageenan-inflamed air pouches, and markedly inhibited leukocyte accumulation in inflamed air pouches. The methotrexate-mediated reduction in leukocyte accumulation was partially reversed by injection of adenosine deaminase (ADA) into the air pouch, completely reversed by a specific adenosine A2 receptor antagonist, 3,7-dimethyl-l-propargylxanthine (DMPX), but not affected by an adenosine Al receptor antagonist, 8-cyclopentyl-dipropylxanthine. Neither ADA nor DMPX affected leukocyte accumulation in the inflamed pouches of animals treated with either saline or the potent antiinflammatory steroid dexamethasone. These results indicate that methotrexate is a nonsteroidal antiinflammatory agent, the antiphlogistic action of which is due to increased adenosine release at inflamed sites. (J. Clin. Invest. 1993Invest. . 92:2675Invest. -2682

The effect of genotype on methotrexate polyglutamate variability in juvenile idiopathic arthritis and association with drug response

“…In this multivariate analysis, the TYMS 6-nucleotide deletion (rs11280056) remained associated with cluster outcome, whereas ATIC (rs4673990) and ADORA2a (rs3761422) did not show [3][4][5] . The most pronounced combination of single-nucleotide polymorphisms differentiating subjects in cluster 1 from those in cluster 3 was in the model evaluating ATIC (SNP rs4673990, AϾG) and ADORA2a (SNP rs3761422).…”

“…SNPs within the purine (ATIC) and adenosine (ADORA2a) pathways were found to differentiate clusters with high concentrations (specifically, MTXGlu [3][4][5] ) from those with low overall concentrations. Additionally, with the use of more traditional statistical methods, we identified a SNP in TYMS that was associated with cluster outcome as well.…”

“…To increase specificity and minimize interference with coeluting substances, an ion-pair reverse-phase chromatography method was developed to measure the individual subtypes of MTXGlu (MTXGlu 1-7 ) in human RBCs (14). Since MTXGlu 1-5 accounted for 99.6% of MTXGlu total , subsequent analyses assessed MTXGlu [1][2][3][4][5] .…”

Le neutrophile : ennemi ou ami ?

“…Un changement phénotypique L'adénosine inhibe l'adhérence des PN à la paroi endothéliale [22], ainsi que l'explosion oxydative et la dégranulation [23]. L'activation du récepteur A 2A par ce nucléoside provoque un changement majeur dans le profil de sécrétion des médiateurs lipidiques par les PN (Figure 2).…”

Eficácia terapêutica do Metotrexato na Artrite Reumatóide depende da expressão de células T reguladoras CD39+?

“…Trabalhos também propõem que a eficácia terapêutica observada com a administração de baixas doses de MTX, é decorrente de sua capacidade em manter e aumentar os níveis de adenosina extracelular (Cronstein et al, 1993;Morabito et al, 1998 (Thiel et al, 1996), adesão (Cronstein et al, 1990), produção dos radicais de oxigênio (Cronstein et al, 1985), degranulação (Richter, 1992) e produção de TNF-α (Thiel & Chouker, 1995 Tregs, e conseqüentemente, ocasionar a geração de células T ativadas refratárias à supressão mediada pela adenosina (Bansard et al, 2009). …”