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Review
. 2019 Oct 10;20(20):5023.
doi: 10.3390/ijms20205023.

Methotrexate an Old Drug with New Tricks

Yosra Bedoui  1 , Xavier Guillot  2 , Jimmy Sélambarom  3 , Pascale Guiraud  4 , Claude Giry  5 , Marie Christine Jaffar-Bandjee  6 , Stéphane Ralandison  7 , Philippe Gasque  8   9
Affiliations
Review

Methotrexate an Old Drug with New Tricks

Yosra Bedoui et al. Int J Mol Sci. .

Abstract

Methotrexate (MTX) is the first line drug for the treatment of a number of rheumatic and non-rheumatic disorders. It is currently used as an anchor disease, modifying anti-rheumatic drug in the treatment of rheumatoid arthritis (RA). Despite the development of numerous new targeted therapies, MTX remains the backbone of RA therapy due to its potent efficacy and tolerability. There has been also a growing interest in the use of MTX in the treatment of chronic viral mediated arthritis. Many viruses-including old world alphaviruses, Parvovirus B19, hepatitis B/C virus, and human immunodeficiency virus-have been associated with arthritogenic diseases and reminiscent of RA. MTX may provide benefits although with the potential risk of attenuating patients' immune surveillance capacities. In this review, we describe the emerging mechanisms of action of MTX as an anti-inflammatory drug and complementing its well-established immunomodulatory activity. The mechanisms involve adenosine signaling modulation, alteration of cytokine networks, generation of reactive oxygen species and HMGB1 alarmin suppression. We also provide a comprehensive understanding of the mechanisms of MTX toxic effects. Lastly, we discussed the efficacy, as well as the safety, of MTX used in the management of viral-related rheumatic syndromes.

Keywords: alarmin; arthritis; chikungunya; inflammation; innate immunity; methotrexate; pharmacology; rheumatoid arthritis; virus.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Pharmacokinetic process of MTX after oral administration. MTX absorption, distribution, metabolism, and excretion after oral administration.
Figure 2
Figure 2
Methotrexate (MTX) transporters, metabolic pathways and intracellular enzyme targets. MTX transport across biological membranes is mediated by the reduced folate carrier (RFC1), the proton-coupled folate transporter (PCFT) (mainly expressed in the proximal part of the small intestine at the apical membrane of enterocytes) with limited contribution of folate receptors (FR). MTX is exported from the cell by the ATP-binding cassette (ABCC)-family transporters. Within the cell, MTX is converted to polyglutamate forms in a reversible reaction mediated by folylpolyglutamate synthetase (FPGS) and γ-glutamyl hydrolase (GGH). Polyglutamation reduces MTX efflux from the cell via ABCC transporters and therefore increases intracellular half-life of MTX. Intracellular formation of MTX polyglutamate also plays a critical role in MTX activity, increasing inhibition of dihydrofolate reductase (DHFR) and several folate dependent enzymes such as thymidylate synthase (TYMS), 5-amino-imidazole-4-carboxide ribonucleotide (AICAR) transformylase (ATIC), and methylene tetrahydrofolate reductase (MTHFR) decreasing downstream folate pathway intermediates required for nucleotide synthesis. DHF, dihydrofolate; THF, tetrahydrofolate; FAICAR, formyl AICAR; MS, methionine synthetase; dTMP, deoxythymidine monophosphate.
Figure 3
Figure 3
Immune regulatory action of low dose MTX in the RA synovial tissue. MTX treatment reduces proinflammatory monocytic/macrophagic cytokine (IL1β, IL6, and TNF-α) production, increases Th2 anti-inflammatory cytokine (IL4 and L10) gene expression, and decreases Th1 proinflammatory cytokine (IL2 and IFNγ) gene expression. MTX downregulates IgG Fc receptors FcγRI and IIa expression levels on monocytes decreasing their activation. MTX seems to disrupt synovial fibroblasts and T cells cross-talk signals by inducing inhibition of IL15, IL6, and IL8 expression by synovial fibroblasts, as well as IFNγ and IL17 expression in co-cultured RA T lymphocytes. MTX increases ROS synthesis in T cells, monocytes and neutrophils. MTX reduces T cells and monocytes growth and increases their apoptosis through the generation of ROS. MTX seems to have inhibitory effect on prostaglandin E2 (PGE2) production as well as on the expression of its synthesizing enzymes microsomal prostaglandin E2 synthase 1 (mPGES-1) and cyclooxygenase (COX) 2. MTX reduces synovial metalloproteinase (MMP) production and stimulates their inhibitors (TIMPs).
Figure 4
Figure 4
MTX affects several signal transduction pathways implicated in the pathogenesis of rheumatoid arthritis (RA). Dysfunctional intracellular signaling involving deregulated activation of the Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) and nuclear factor-κB (NF-κB) activation pathways play a critical role in RA. MTX seems to be a potent suppressor of JAK/STAT signaling pathway which is responsible for the transduction of multiple pro-inflammatory cytokines implicated in the pathogenesis of RA. MTX reduces JAK1, JAK2, STAT1, and STAT5 phosphorylation. Low dose MTX strongly suppresses levels of phosphorylated STAT5. Moreover, MTX-mediated ROS production activates the mitogen-activated protein kinase (MAPK), Jun-N-terminal kinase (JNK), and JNK-dependent induction of p53, which is the final mediator of inhibition of NF-κB activation. NF-κB is involved in inflammation, immune response and cell proliferation and survival. MTX-mediated JNK activation also activates prototypical JNK downstream targets, c-JUN and c-FOS, components of the AP-1 complex which is involved in the increased expression of pro apoptotic genes (such as TNF-α, Fas-L, and Bak) mediating increased sensitivity of cells to apoptosis.
Figure 5
Figure 5
MTX inhibits HMGB-1/RAGE interaction. HMGB1 released by activated immune cells (macrophages, monocytes, and dendritic cells) or by injured cells acts as an important mediator of inflammation or alarmin. HMGB-1 activates cells through the engagement of multiple surface receptors including TLR2, TLR4, and RAGE. Downstream signaling of HMGB1 is mediated by a number of adaptor proteins, which converge through pathways involving mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NFκB) and transcriptional regulator, p53 pathways (Weber et al. 2015). HMGB-1 signaling through RAGE promotes maturation of immune cells, chemotaxis and release of pro-inflammatory cytokines (TNF-α, IL-1, IL-6, and IL-8). MTX can bind to the RAGE binding domains of HMGB1 and inhibits the interaction between HMGB1 and its receptor RAGE, thus inhibiting the development of inflammatory responses. Binding of MTX to part of the RAGE-binding region in HMGB1 may be significant for the anti-inflammatory effect of MTX.
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