The anti‐inflammatory actions of methotrexate are critically dependent upon the production of reactive oxygen species

@article{Phillips2003TheAA,
  title={The anti‐inflammatory actions of methotrexate are critically dependent upon the production of reactive oxygen species},
  author={Darren Charles Phillips and Kevin J. Woollard and Helen R. Griffiths},
  journal={British Journal of Pharmacology},
  year={2003},
  volume={138}
}
The mechanism of action by which methotrexate (MTX) exerts its anti‐inflammatory and immunosuppressive effects remains unclear. The aim of this study is to investigate the hypothesis that MTX exerts these effects via the production of reactive oxygen species (ROS). Addition of MTX (100 nM–10 μM) to U937 monocytes induced a time and dose dependent increase in cytosolic peroxide [peroxide]cyt from 6–16 h. MTX also caused corresponding monocyte growth arrest, which was inhibited (P<0.05) by pre… 
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Ornithine decarboxylase prevents methotrexate-induced apoptosis by reducing intracellular reactive oxygen species production

It is found MTX could induce caspase-dependent apoptosis and promote ROS generation together with disrupting the mitochondrial membrane potential of HL-60 and Jurkat T cells and demonstrate that MTX-induced apoptosis is ROS-dependent and occurs along a mitochondria-mediated pathway.

Low dose methotrexate induces apoptosis with reactive oxygen species involvement in T lymphocytic cell lines to a greater extent than in monocytic lines

The high susceptibility of T cell lines to MTX induced apoptosis may account for the beneficial effect of MTX treatment in rheumatoid arthritis, which is characterized by hyperproliferation of T cells.

Lutein Protects against Methotrexate-Induced and Reactive Oxygen Species-Mediated Apoptotic Cell Injury of IEC-6 Cells

The MTX-induced apoptosis of IEC-6 cells was shown to be repressed by the pre-treatment of lutein, which may represent a promising adjunct to conventional chemotherapy for preventing intestinal damages.

Increased sensitivity to apoptosis induced by methotrexate is mediated by JNK.

The finding of increased jun levels in patients with RA receiving low-dose MTX supports the notion that this pathway is activated byMTX in vivo and may contribute to the efficacy of MTX in inflammatory disease.

Protective effect of Chlorogenic acid against methotrexate induced oxidative stress, inflammation and apoptosis in rat liver: An experimental approach.

Protective Effects of Exogenous Melatonin Against Methotrexate-Induced Intestinal Injury

It is demonstrated that supplementation by exogenous melatonin significantly reduces MTX-induced small intestinal damage, indicating that it may be beneficial in ameliorating MTx-induced enteritis in humans.

Impact of methotrexate on oxidative stress and apoptosis markers in psoriatic patients

MTX induce apoptosis through oxidative stress by reducing NO and increasing caspase-3 levels, which may account for the beneficial effect of MTX treatment in psoriasis patients, which is characterized by acanthosis.

Methotrexate induces production of IL-1 and IL-6 in the monocytic cell line U937

MTX induces expression of proinflammatory cytokines in U937 monocytic cells and might mediate the known toxicities of MTX including pneumonitis, mucositis and decreased bone mineral density.

Protective Effects of Alpha-Lipoic Acid on Methotrexate-Induced Oxidative Lung Injury in Rats

  • H. ArpagM. Gül M. Sayan
  • Medicine
    Journal of investigative surgery : the official journal of the Academy of Surgical Research
  • 2018
Oxidative damage of MTX in rat lung is partially reduced when combined with Alpha-lipoic acid, which occurs naturally in human food and has antioxidative and anti-inflammatory activities.

Increased sensitivity to apoptosis induced by methotrexate is mediated by Jun N-terminal kinase

The finding of increased JUN levels in subjects with RA taking low-dose MTX supports the notion that this pathway is activated by MTX, in vivo, and may contribute to efficacy of MTX in inflammatory disease.
...

96 References

Pro-oxidant properties of methotrexate: evaluation and prevention by an anti-oxidant drug.

This in vitro study demonstrates that methotrexate (MTX), an anticancer drug, increases the amount of hydrogen peroxide released by stimulated PMNs in a dose-dependent manner with a maximum increase of 43.7%.

Inducers of cytochrome P450 2E1 enhance methotrexate-induced hepatocytoxicity.

Methotrexate: pentose cycle and oxidative stress

The net results appear to show that the biological situation resulting from treatment with MTX leads to a reduction of effectiveness of the antioxidant enzyme defence system.

Immunosuppressive properties of methotrexate: apoptosis and clonal deletion of activated peripheral T cells.

The data demonstrate that MTX can selectively delete activated peripheral blood T cells by a CD95-independent pathway, and this property could be used as a new pharmacological end point to optimize dosage and timing of MTX administration.

Anti-arthritic effect of methotrexate: is it really mediated by adenosine?

Auranofin inhibits the induction of interleukin 1β and tumor necrosis factor α mRNA in macrophages

The effect of methotrexate on lipoxygenase metabolism in neutrophils from rats:In vitro andex vivo studies

Inhibition of 5-LO metabolism does not appear to explain the anti-inflammatory effects of MTX, and no inhibition of LTB4 production was seen followingin vivo administration ofMTX by oral, subcutaneous or intraperitoneal routes.

Auranofin inhibits the induction of interleukin 1 beta and tumor necrosis factor alpha mRNA in macrophages.

The auranofin-mediated inhibition of the induction of TNF-alpha mRNA was stronger than that of interleukin (IL) 1 beta mRNA and also inhibited zymosan-induced mobilization of arachidonate.

The effect of methotrexate on ex vivo lipoxygenase metabolism in neutrophils from patients with rheumatoid arthritis.

The results do not support the putative inhibitory effect of MTX on 5-LO metabolism and an increase in the production of all measured 5- LO metabolites was seen between the pre and postdose assessments.

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

Results indicate that methotrexate is a nonsteroidal antiinflammatory agent, the antiphlogistic action of which is due to increased adenosine release at inflamed sites.
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