Comprehensive analysis of gene expression and DNA methylation datasets identify valuable biomarkers for rheumatoid arthritis progression

Fang, Gang; Zhang, Qing Huai; Tang, Qianqian; Jiang, Zuling; Xing, Shasha; Li, Jianying; Pang, Yuzhou

doi:10.18632/oncotarget.22918

Cited by 11 publications

(9 citation statements)

References 42 publications

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“…RA may involve defects in acetylation (212), reflected in the beneficial activity of a histone deacetylase inhibitor in CIA (213). It is also likely that there are changes in DNA methylation (214)(215)(216)(217) as has been noted in regulatory T cells (218) and synovial fibroblasts (219). The methylation pattern has been claimed to reflect therapeutic efficacy of the TNF-α inhibitor etanercept (220) and so may be relevant to explaining the nonresponsiveness to this drug of some patients.…”

Section: Epigenetics Of Idomentioning

confidence: 98%

IDO and Kynurenine Metabolites in Peripheral and CNS Disorders

et al. 2020

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The importance of the kynurenine pathway in normal immune system function has led to an appreciation of its possible contribution to autoimmune disorders such as rheumatoid arthritis. Indoleamine-2,3-dioxygenase (IDO) activity exerts a protective function, limiting the severity of experimental arthritis, whereas deletion or inhibition exacerbates the symptoms. Other chronic disorder with an inflammatory component, such as atherosclerosis, are also suppressed by IDO activity. It is suggested that this overall anti-inflammatory activity is mediated by a change in the relative production or activity of Th17 and regulatory T cell populations. Kynurenines may play an anti-inflammatory role also in CNS disorders such as Huntington's disease, Alzheimer's disease and multiple sclerosis, in which signs of inflammation and neurodegeneration are involved. The possibility is discussed that in Huntington's disease kynurenines interact with other anti-inflammatory molecules such as Human Lymphocyte Antigen-G which may be relevant in other disorders. Kynurenine involvement may account for the protection afforded to animals with cerebral malaria and trypanosomiasis when they are treated with an inhibitor of kynurenine-3-monoxygenase (KMO). There is some evidence that changes in IL-10 may contribute to this protection and the relationship between kynurenines and IL-10 in arthritis and other inflammatory conditions should be explored. In addition, metabolites of kynurenine downstream of KMO, such as anthranilic acid and 3-hydroxy-anthranilic acid can influence inflammation, and the ratio of these compounds is a valuable biomarker of inflammatory status although the underlying molecular mechanisms of the changes require clarification. Hence it is essential that more effort be expended to identify their sites of action as potential targets for drug development. Finally, we discuss increasing awareness of the epigenetic regulation of IDO, for example by DNA methylation, a phenomenon which may explain differences between individuals in their susceptibility to arthritis and other inflammatory disorders.

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Section: Epigenetics Of Idomentioning

confidence: 98%

IDO and Kynurenine Metabolites in Peripheral and CNS Disorders

et al. 2020

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“…Importantly, if epigenetic changes affect the germ-line cells of an individual, they may be inherited by the offspring and modify their susceptibility to external influences and disease. Changes in DNA methylation status have been observed in RA [96][97][98][99][100] where the extent of methylation may determine patient responsivity to the TNF-α inhibitor drug etanercept 101 . RA may also involve abnormalities in acetylation status 102 , emphasised by the ability of a histone deacetylase inhibitor to inhibit symptoms in the collagen-induced model of arthritis 103 .…”

Section: Summary and Future Directionsmentioning

confidence: 99%

IDO activation, inflammation and musculoskeletal disease

Ogbechi

Clanchy

Huang

et al. 2020

Experimental Gerontology

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The IDO/kynurenine pathway is now established as a major regulator of immune system function. The initial enzyme, indoleamine 2,3-dioxygenase (IDO1) is induced by IFNγ, while tryptophan-2,3-dioxygenase (TDO) is induced by corticosteroids. The pathway is therefore positioned to mediate the effects of systemic inflammation or stress-induced steroids on tissue function and its expression increases with age. Disorders of the musculoskeletal system are a common feature of aging and many of these conditions are characterized by an inflammatory state. In inflammatory arthritis and related disorders, kynurenine protects against the development of experimental arthritis, while inhibition or deletion of IDO1 increases its severity. The longterm regulation of autoimmune disorders may be influenced by the epigenetic modulation of kynurenine pathway genes, with recent data suggesting that methylation of IDO may be involved. Osteoporosis is also associated with abnormalities of the kynurenine pathway, reflected in an inversion of the ratio between blood levels of the metabolites anthranilic acid and 3-hydroxy-anthranilic acid. This review discusses evidence to date on the role of the IDO/kynurenine pathway and the highly prevalent age-related disorders of osteoporosis and rheumatoid arthritis and identifies key areas that require further research.

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“…In addition to the possible reduction of these compounds, spermine suppresses LFA-1 expression via regulation of gene methylation. Because inflammation is also closely associated with gene methylation [ 44 , 368 , 369 , 370 , 371 ], suppression of immune cell activation may counteract the progression of aging-associated pathologies.…”

Section: Future Perspectivesmentioning

confidence: 99%

Polyamine Metabolism and Gene Methylation in Conjunction with One-Carbon Metabolism

Soda

2018

IJMS

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Recent investigations have revealed that changes in DNA methylation status play an important role in aging-associated pathologies and lifespan. The methylation of DNA is regulated by DNA methyltransferases (DNMT1, DNMT3a, and DNMT3b) in the presence of S-adenosylmethionine (SAM), which serves as a methyl group donor. Increased availability of SAM enhances DNMT activity, while its metabolites, S-adenosyl-l-homocysteine (SAH) and decarboxylated S-adenosylmethionine (dcSAM), act to inhibit DNMT activity. SAH, which is converted from SAM by adding a methyl group to cytosine residues in DNA, is an intermediate precursor of homocysteine. dcSAM, converted from SAM by the enzymatic activity of adenosylmethionine decarboxylase, provides an aminopropyl group to synthesize the polyamines spermine and spermidine. Increased homocysteine levels are a significant risk factor for the development of a wide range of conditions, including cardiovascular diseases. However, successful homocysteine-lowering treatment by vitamins (B6, B12, and folate) failed to improve these conditions. Long-term increased polyamine intake elevated blood spermine levels and inhibited aging-associated pathologies in mice and humans. Spermine reversed changes (increased dcSAM, decreased DNMT activity, aberrant DNA methylation, and proinflammatory status) induced by the inhibition of ornithine decarboxylase. The relation between polyamine metabolism, one-carbon metabolism, DNA methylation, and the biological mechanism of spermine-induced lifespan extension is discussed.

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Comprehensive analysis of gene expression and DNA methylation datasets identify valuable biomarkers for rheumatoid arthritis progression

Cited by 11 publications

References 42 publications

IDO and Kynurenine Metabolites in Peripheral and CNS Disorders

IDO and Kynurenine Metabolites in Peripheral and CNS Disorders

IDO activation, inflammation and musculoskeletal disease

Polyamine Metabolism and Gene Methylation in Conjunction with One-Carbon Metabolism

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