Methylene tetrahydrofolate reductase, transforming growth factor-β1 and lymphotoxin-α genes polymorphisms and susceptibility to rheumatoid arthritis

While Lymphotoxin α (TNF-β), a product of lymphocytes, is known to play a pivotal role in inflammatory joint environment, resveratrol has been shown to possess anti-inflammatory and chondroprotective effects via activation of the histondeacetylase Sirt1. Whether TNF-β induction of inflammatory pathways in primary human chondrocytes (PCH) can be modulated by resveratrol, was investigated. Monolayer and alginate cultures of PCH were treated with TNF-β, anti-TNF-β, nicotinamide (NAM), antisense oligonucleotides against Sirt1 (Sirt1-ASO) and/or resveratrol and co-cultured with T-lymphocytes. We found that resveratrol suppressed, similar to anti-TNF-β, TNF-β-induced increased adhesiveness in an inflammatory microenvironment of T-lymphocytes and PCH. In contrast, knockdown of Sirt1 by mRNA abolished the inhibitory effects of resveratrol on the TNF-β-induced adhesiveness, suggesting the essential role of this enzyme for resveratrol-mediated anti-inflammatory signaling. Similar results were obtained in PCH stimulated with TNF-α. Sirt1-ASO, NAM or TNF-β, similar to T-lymphocytes induced inflammatory microenvironment by down-regulation of cartilage-specific proteins, Sox9, Ki67 and enhanced NF-κB-regulated gene products involved in inflammatory and degradative processes in cartilage (MMP-9/-13, COX-2, caspase-3), NF-κB activation and its translocation to the nucleus. Moreover, resveratrol reversed the TNF-β-, NAM-, T-lymphocytes-induced up-regulation of various NF-κB-regulated gene products. Down-regulation of Sirt1 by mRNA interference abrogated the effect of resveratrol on TNF-β-induced effects. Ultrastructural and cell viability assay investigations revealed that resveratrol revoked TNF-β-induced dose-dependent degradative/apoptotic morphological changes, cell viability and proliferation in PCH. Taken together, suppression of TNF-β-induced inflammatory microenvironment in PCH by resveratrol/Sirt1 might be a novel therapeutic approach for targeting inflammation during rheumatoid arthritis.

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“…Interestingly, recently Shaker et al . have further shown that polymorphisms in the TNF-β gene increase susceptibility to RA [ 56 ].…”

Section: Discussionmentioning

confidence: 99%

Resveratrol downregulates inflammatory pathway activated by lymphotoxin α (TNF-β) in articular chondrocytes: Comparison with TNF-α

Buhrmann¹,

Popper²,

Aggarwal

et al. 2017

PLoS ONE

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“…A more recent study found a significant higher frequency of lymphotoxin-α (LTα) (+252) AG phenotype in 17 AIHA cases compared to controls (41% vs. 13%) (69). LT-α (also known as TNF-β), is involved in the regulation of cell survival, proliferation, differentiation, and apoptosis, and plays an important role in innate immune regulation and immune-surveillance (98).…”

Section: Studies On Cell-mediated Immunitymentioning

confidence: 99%

Autoimmune Cytopenias in Chronic Lymphocytic Leukemia: Focus on Molecular Aspects

Fattizzo

Barcellini

2020

Front. Oncol.

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Autoimmune cytopenias, particularly autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP), complicate up to 25% of chronic lymphocytic leukemia (CLL) cases. Their occurrence correlates with a more aggressive disease with unmutated VHIG status and unfavorable cytogenetics (17p and 11q deletions). CLL lymphocytes are thought to be responsible of a number of pathogenic mechanisms, including aberrant antigen presentation and cytokine production. Moreover, pathogenic B-cell lymphocytes may induce T-cell subsets imbalance that favors the emergence of autoreactive B-cells producing anti-red blood cells and anti-platelets autoantibodies. In the last 15 years, molecular insights into the pathogenesis of both primary and secondary AIHA/ITP has shown that autoreactive B-cells often display stereotyped B-cell receptor and that the autoantibodies themselves have restricted phenotypes. Moreover, a skewed T-cell repertoire and clonal T cells (mainly CD8+) may be present. In addition, an imbalance of T regulatory-/T helper 17-cells ratio has been involved in AIHA and ITP development, and correlates with various cytokine genes polymorphisms. Finally, altered miRNA and lnRNA profiles have been found in autoimmune cytopenias and seem to correlate with disease phase. Genomic studies are limited in these forms, except for recurrent mutations of KMT2D and CARD11 in cold agglutinin disease, which is considered a clonal B-cell lymphoproliferative disorder resulting in AIHA. In this manuscript, we review the most recent literature on AIHA and ITP secondary to CLL, focusing on available molecular evidences of pathogenic, clinical, and prognostic relevance.

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“…So far, several single nucleotide polymorphisms (SNPs) in different known loci such as NUBPL (rs2378945), NCTN5 (rs1813443), PLA2G4A (rs12142623 and rs4651370) [ 21 ], LINC02549 (rs7767069), LARRC55 (rs717117G) [ 22 ], MED15 (rs113878252), MAFB (rs6065221) [ 23 ], CD84 (rs6427528 and rs1503860) [ 24 ], TNF (rs1800629), EYA4 (rs17301249) [ 25 ], PDZD2 (rs1532269) [ 26 ], and CCL21 (rs2812378) [ 27 ] genes or in unknown loci, including rs4411591, rs7767069, rs1447722, and rs1568885 [ 21 ], have been identified, which are associated with a response to anti-TNF treatments in RA. The evidence supports an association between SNPs in the MTHFR genes c.665C>T (rs1801133, historically referred to as c.677C>T or C677T) and c.1298A>C (rs1801131) and the occurrence risk of RA [ 28 , 29 , 30 ] or the expression of inflammation markers [ 31 , 32 ], conditions during which inflammatory cytokines such as TNF-α, which is the direct target of TNF-α inhibitor drugs, play a fundamental role [ 33 ]. However, further studies addressing the association of these polymorphisms with the response to TNF-α inhibitor drugs in RA patients have not been performed.…”

Section: Introductionmentioning

confidence: 76%

“…Both variants are associated with a higher expression of inflammation markers [ 31 , 32 ] and the risk of occurrence of RA [ 28 , 29 , 30 ]. Although the exact mechanism of the association of these two SNPs with systemic inflammation is not known, possible explanations point to an increased level of tHcy, which is correlated with serum C4, CRP, and the IgM level [ 40 ] as well as increased oxidative stress [ 41 , 42 ] and DNA hypomethylation [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

MTHFR c.665C>T and c.1298A>C Polymorphisms in Tailoring Personalized Anti-TNF-α Therapy for Rheumatoid Arthritis

Ravaei

Pulsatelli

Assirelli

et al. 2023

IJMS

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Rheumatoid arthritis (RA) is an inflammatory autoimmune disease with a prevalence of 1%. Currently, RA treatment aims to achieve low disease activity or remission. Failure to achieve this goal causes disease progression with a poor prognosis. When treatment with first-line drugs fails, treatment with tumor necrosis factor-α (TNF-α) inhibitors may be prescribed to which many patients do not respond adequately, making the identification of response markers urgent. This study investigated the association of two RA-related genetic polymorphisms, c.665C>T (historically referred to as C677T) and c.1298A>C, in the MTHFR gene as response markers to an anti-TNF-α therapy. A total of 81 patients were enrolled, 60% of whom responded to the therapy. Analyses showed that both polymorphisms were associated with a response to therapy in an allele dose-dependent manner. The association for c.665C>T was significant for a rare genotype (p = 0.01). However, the observed opposite trend of association for c.1298A>C was not significant. An analysis revealed that c.1298A>C, unlike c.665C>T, was also significantly associated with the drug type (p = 0.032). Our preliminary results showed that the genetic polymorphisms in the MTHFR gene were associated with a response to anti-TNF-α therapy, with a potential significance for the anti-TNF-α drug type. This evidence suggests a role for one-carbon metabolism in anti-TNF-α drug efficacy and contributes to further personalized RA interventions.

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Methylene tetrahydrofolate reductase, transforming growth factor-β1 and lymphotoxin-α genes polymorphisms and susceptibility to rheumatoid arthritis

Abstract: Our findings suggest that there is association between MTHFR C677 T and LT-α A252G genes polymorphisms and increased risk of RA in this sample of Egyptian population.

Cited by 3 publications

References 38 publications

Resveratrol downregulates inflammatory pathway activated by lymphotoxin α (TNF-β) in articular chondrocytes: Comparison with TNF-α

Resveratrol downregulates inflammatory pathway activated by lymphotoxin α (TNF-β) in articular chondrocytes: Comparison with TNF-α

Autoimmune Cytopenias in Chronic Lymphocytic Leukemia: Focus on Molecular Aspects

MTHFR c.665C>T and c.1298A>C Polymorphisms in Tailoring Personalized Anti-TNF-α Therapy for Rheumatoid Arthritis

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