Therapeutic approaches for tumor necrosis factor inhibition

Barbosa, Maria Letícia de Castro; Fumian, Milla Machado; Miranda, Ana Luísa P.; Barreiro, Eliezer J.; Lima, Lı́dia Moreira

doi:10.1590/s1984-82502011000300002

Cited by 18 publications

(8 citation statements)

References 92 publications

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“…The TNFRSF1a is an established receptor for soluble TNFα, and it has also been reported that mutation in TNFRSF1a decreases TNFα-induced apoptosis. 32 38 39 TNFα is regulated by the transcription factor, NF-kB, 40 and we observed that loss of MLK3 was able to induce NF-kB in CD4 + T cells, and therefore, we can speculate that induction of NF-kB can increase TNFα production due to loss of MLK3. We also observed that loss of MLK3 induced CD70 expression on T cells, and it is reported that treatment of human peripheral blood mononuclear cells with CD70 induces rapid decrease of inhibitor of kappa B (IκBα), indicating that CD70-CD27 axis can trigger activation of the canonical NF-kB pathway and this could result in TNFα induction/synthesis.…”

Section: Discussionmentioning

confidence: 90%

Rationalized inhibition of mixed lineage kinase 3 and CD70 enhances life span and antitumor efficacy of CD8⁺T cells

Kumar

Singh

Viswakarma

et al. 2020

J Immunother Cancer

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BackgroundThe mitogen-activated protein kinases (MAPKs) are important for T cell survival and their effector function. Mixed lineage kinase 3 (MLK3) (MAP3K11) is an upstream regulator of MAP kinases and emerging as a potential candidate for targeted cancer therapy; yet, its role in T cell survival and effector function is not known.MethodsT cell phenotypes, apoptosis and intracellular cytokine expressions were analyzed by flow cytometry. The apoptosis-associated gene expressions in CD8+CD38+ T cells were measured using RT2 PCR array. In vivo effect of combined blockade of MLK3 and CD70 was analyzed in 4T1 tumor model in immunocompetent mice. The serum level of tumor necrosis factor-α (TNFα) was quantified by enzyme-linked immunosorbent assay.ResultsWe report that genetic loss or pharmacological inhibition of MLK3 induces CD70-TNFα-TNFRSF1a axis-mediated apoptosis in CD8+ T cells. The genetic loss of MLK3 decreases CD8+ T cell population, whereas CD4+ T cells are partially increased under basal condition. Moreover, the loss of MLK3 induces CD70-mediated apoptosis in CD8+ T cells but not in CD4+ T cells. Among the activated CD8+ T cell phenotypes, CD8+CD38+ T cell population shows more than five fold increase in apoptosis due to loss of MLK3, and the expression of TNFRSF1a is significantly higher in CD8+CD38+ T cells. In addition, we observed that CD70 is an upstream regulator of TNFα-TNFRSF1a axis and necessary for induction of apoptosis in CD8+ T cells. Importantly, blockade of CD70 attenuates apoptosis and enhances effector function of CD8+ T cells from MLK3−/− mice. In immune-competent breast cancer mouse model, pharmacological inhibition of MLK3 along with CD70 increased tumor infiltration of cytotoxic CD8+ T cells, leading to reduction in tumor burden largely via mitochondrial apoptosis.ConclusionTogether, these results demonstrate that MLK3 plays an important role in CD8+ T cell survival and effector function and MLK3-CD70 axis could serve as a potential target in cancer.

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Section: Discussionmentioning

confidence: 90%

Rationalized inhibition of mixed lineage kinase 3 and CD70 enhances life span and antitumor efficacy of CD8⁺T cells

Kumar

Singh

Viswakarma

et al. 2020

J Immunother Cancer

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“…An alternative to TNF-a hyper-response modulation in COVID-19 infections is the use of anti-TNF-a antibodies (75). However, most drugs that target TNF-a also block bioavailable TNF-a that monocytes and T cells produce, increasing the susceptibility to viral or bacterial coinfection or reinfection (76). AM3 normalizes the TNF-a production (27); in particular, AM3 inhibited TNF-a production by 90% compared to sera from placebo-treated mice.…”

Section: Am3 and Cytokinesmentioning

confidence: 99%

Glycophosphopeptical AM3 Food Supplement: A Potential Adjuvant in the Treatment and Vaccination of SARS-CoV-2

Fernández-Lázaro

Adams

et al. 2021

Front. Immunol.

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The world is currently experiencing the coronavirus disease 2019 (COVID-19) pandemic caused by Severe Acute Respiratory Syndrome-2 (SARS-CoV-2). Its global spread has resulted in millions of confirmed infections and deaths. While the global pandemic continues to grow, the availability of drugs to treat COVID-19 infections remains limited to supportive treatments. Moreover, the current speed of vaccination campaigns in many countries has been slow. Natural substrates with biological immunomodulatory activity, such as glucans, may represent an adjuvant therapeutic agent to treat SARS-CoV-2. AM3, a natural glycophosphopeptical, has previously been shown to effectively slow, with no side effects, the progression of infectious respiratory diseases by regulating effects on innate and adaptive immunity in experimental models. No clinical studies, however, exist on the use of AM3 in SARS-CoV-2 infected patients. This review aims to summarize the beneficial effects of AM3 on respiratory diseases, the inflammatory response, modulation of immune response, and attenuation of muscle. It will also discuss its potential effects as an immune system adjuvant for the treatment of COVID-19 infections and adjuvant for SARS-CoV-2 vaccination.

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“…They resulted in higher and constitutive TNF-α expression and were associated with an increased risk of HCC [ 10 , 17 ]. TNF-α itself is a potent pro-inflammatory cytokine [ 17 , 59 ]. Necroinflammation in hepatocytes triggers mutagenesis and activation of oncogenes from proto-oncogenes in host cells, causing HCC [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

Association between five types of Tumor Necrosis Factor-α gene polymorphism and hepatocellular carcinoma risk: a meta-analysis

et al. 2020

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Background Research focusing on the relationship between five types of tumor necrosis factor-alpha (TNF-α) SNPs and the risk of hepatocellular carcinoma (HCC) were still controversial. Hereby, we performed a meta-analysis to determine the association between TNF-α promoter SNPs: -1031 T/C, − 863 C/A, − 857 C/T, − 308 G/A, and − 238 G/A with HCC risk. Methods We interrogated articles from journal database: PubMed, Pro-Quest, EBSCO, Science Direct, and Springer to determine the relationship between five types of SNPs in TNF-α gene with HCC risk. RevMan 5.3 software was used for analysis in fixed/random effect models. Results This meta-analysis included 23 potential articles from 2004 to 2018 with 3237 HCC cases and 4843 controls. We found that SNP − 863 C/A were associated with a significantly increased HCC risk (A vs C, OR = 1.31, 95% CI = 1.03–1.67). Similar results were obtained in − 857 C/T (TT/CT vs CC, OR = 1.31, 95% CI = 1.06–1.62), − 308 G/A (AA vs GG, OR = 3.14, 95% CI = 2.06–4.79), and − 238 G/A (AA vs GG, OR = 3.87, 95% CI = 1.32–11.34). While no associations were observed between SNP TNF-α − 1031 T/C and HCC risk. Conclusions The present meta-analysis showed that TNFα SNPs -863C/A, − 857 C/T, − 308 G/A, and − 238 G/A were associated with the risk of HCC.

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Therapeutic approaches for tumor necrosis factor inhibition

Cited by 18 publications

References 92 publications

Rationalized inhibition of mixed lineage kinase 3 and CD70 enhances life span and antitumor efficacy of CD8⁺T cells

Rationalized inhibition of mixed lineage kinase 3 and CD70 enhances life span and antitumor efficacy of CD8⁺T cells

Glycophosphopeptical AM3 Food Supplement: A Potential Adjuvant in the Treatment and Vaccination of SARS-CoV-2

Association between five types of Tumor Necrosis Factor-α gene polymorphism and hepatocellular carcinoma risk: a meta-analysis

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Therapeutic approaches for tumor necrosis factor inhibition

Cited by 18 publications

References 92 publications

Rationalized inhibition of mixed lineage kinase 3 and CD70 enhances life span and antitumor efficacy of CD8+T cells

Rationalized inhibition of mixed lineage kinase 3 and CD70 enhances life span and antitumor efficacy of CD8+T cells

Glycophosphopeptical AM3 Food Supplement: A Potential Adjuvant in the Treatment and Vaccination of SARS-CoV-2

Association between five types of Tumor Necrosis Factor-α gene polymorphism and hepatocellular carcinoma risk: a meta-analysis

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Rationalized inhibition of mixed lineage kinase 3 and CD70 enhances life span and antitumor efficacy of CD8⁺T cells

Rationalized inhibition of mixed lineage kinase 3 and CD70 enhances life span and antitumor efficacy of CD8⁺T cells