Variation in the TNF-α promoter region associated with susceptibility to cerebral malaria

During the last decade, a growing corpus of evidence has indicated an important role of cytokines in the development of brain damage following cerebral ischemia. Tumor necrosis factor-α (TNF-α), a potent immunomodulator and pro-inflammatory cytokine, has been implicated in many pathological processes. In this study, we examined whether promoter region polymorphism in the TNF-α gene at position –308 affects the odds of cerebral infarction (CI) and whether genetic risk is enhanced by Sasang constitutional classification. Two hundred and twelve CI patients and 610 healthy controls were genotyped and determined according to Sasang constitutional classification. A significant decrease was found for the TNF-α A allele in CI patients compared with controls ( p = 0.033, odds ratio, OR: 0.622). However, there was no significant association between TNF-α polymorphism and Sasang constitution in CI patients. Our finding suggests that TNF-α promoter region polymorphism is responsible for susceptibility to CI in Koreans.

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TNF-α Suppressed FSH-Induced LH Receptor Expression Through Transcriptional Regulation in Rat Granulosa Cells

Endocrinology ◽

10.1210/en.2015-1238 ◽

2015 ◽

Vol 156 (9) ◽

pp. 3192-3202 ◽

Cited By ~ 6

Author(s):

Kohshiro Nakao ◽

Hiroshi Kishi ◽

Fumiharu Imai ◽

Hiroto Suwa ◽

Takashi Hirakawa ◽

...

Keyword(s):

Mrna Expression ◽

Granulosa Cells ◽

Promoter Region ◽

Ovarian Function ◽

Receptor Expression ◽

Luciferase Assay ◽

Pelvic Cavity ◽

Transcriptional Level ◽

Lh Receptor ◽

Tnf Α

Several inflammatory cytokines regulate ovarian function. TNF-α is produced in granulosa cells under physiological conditions and has a reciprocal action on follicle development. In contrast, in pelvic inflammatory diseases, TNF-α is excessively produced in the pelvic cavity and has an adverse effect on reproductive functions. The objective of this study was to elucidate the mechanism of action of TNF-α on the expression of LH receptor (LHR) in immature rat granulosa cells. TNF-α suppressed FSH-induced LHR mRNA and protein expression and was not associated with cAMP accumulation. By using a luciferase assay, the construct containing base pairs −1389 to −1 of the rat Lhcgr promoter revealed that TNF-α decreased FSH-induced promoter activity. In response to TNF-α, nuclear factor (NF)-κB p65 was translocated to the nucleus, and the suppressive effect of TNF-α on LHR mRNA expression was abrogated by an NF-κB inhibitor. In a chromatin immunoprecipitation assay, TNF-α induced the association of NF-κB p65 with the rat Lhcgr transcriptional promoter region. NF-κB p65 and histone deacetylase (HDAC) interact to mediate expression of several genes at a transcriptional level. HDAC activity is thought to induce tight connections within local chromatin structures and repress gene transcription. Furthermore, the TNF-α–induced suppression of LHR mRNA expression was blocked by an HDAC inhibitor. Taken together, these results suggest that the interaction of NF-κB p65 with HDAC in the promoter region of rat Lhcgr might be responsible for TNF-α action on the regulation of LHR.

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Genetic Predisposition of the Interleukin-6 Response to Inflammation: Implications for a Variety of Major Diseases?

Clinical Chemistry ◽

10.1373/clinchem.2004.037531 ◽

2004 ◽

Vol 50 (11) ◽

pp. 2136-2140 ◽

Cited By ~ 140

Author(s):

Marie Bennermo ◽

Claes Held ◽

Sten Stemme ◽

Carl-Göran Ericsson ◽

Angela Silveira ◽

...

Keyword(s):

Interleukin 6 ◽

Promoter Region ◽

Insulin Dependent Diabetes Mellitus ◽

Juvenile Chronic Arthritis ◽

In Vivo Studies ◽

Dependent Diabetes Mellitus ◽

Tnf Α

Abstract Background: A single-nucleotide polymorphism (SNP) in the promoter region of the interleukin-6 (IL-6) gene at position −174 (G>C) has been reported to be associated with a variety of major diseases, such as Alzheimer disease, atherosclerosis, and cardiovascular disease, cancer, non-insulin-dependent diabetes mellitus, osteoporosis, sepsis, and systemic-onset juvenile chronic arthritis. However, authors of previous in vitro and in vivo studies have reported conflicting results regarding the functionality of this polymorphism. We therefore aimed to clarify the role of the −174 SNP for the induction of IL-6 in vivo. Methods: We vaccinated 20 and 18 healthy individuals homozygous for the −174 C and G alleles, respectively, with 1 mL of Salmonella typhii vaccine. IL-1β, IL-6, and tumor necrosis factor-α (TNF-α) were measured in the blood at baseline and up to 24 h after vaccination. Results: Individuals with the G genotype had significantly higher plasma IL-6 values at 6, 8, and 10 h after vaccination than did individuals with the C genotype (P <0.005). There were no differences between the two genotypes regarding serum concentrations of IL-1β and TNF-α before or after vaccination. Conclusions: The −174 G>C SNP in the promoter region of the IL-6 gene is functional in vivo with an increased inflammatory response associated with the G allele. Considering the central role of IL-6 in a variety of major diseases, the present finding might be of major relevance.

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Association of cerebral malaria and TNF-α levels: a systematic review

BMC Infectious Diseases ◽

10.1186/s12879-020-05107-2 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Luana Leão ◽

Bruna Puty ◽

Maria Fâni Dolabela ◽

Marinete Marins Povoa ◽

Yago Gecy De Sousa Né ◽

...

Keyword(s):

Systematic Review ◽

Cerebral Malaria ◽

Tnf Α

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-308G>A (rs1800629)and -244G>A(rs673) polymorphisms at the promoter region of the TNF-α gene in severe malaria patients in north-central Nigeria

Nigerian Journal of Parasitology ◽

10.4314/njpar.v38i2.13 ◽

2017 ◽

Vol 38 (2) ◽

pp. 205

Author(s):

S.I. Oyedeji ◽

H.O. Awobode ◽

P.U. Bassi ◽

F.K. Jürgen

Keyword(s):

Severe Malaria ◽

Promoter Region ◽

North Central ◽

Tnf Α

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Interaction between Endothelial Protein C Receptor and Intercellular Adhesion Molecule 1 to Mediate Binding of Plasmodium falciparum -Infected Erythrocytes to Endothelial Cells

mBio ◽

10.1128/mbio.00615-16 ◽

2016 ◽

Vol 7 (4) ◽

Cited By ~ 43

Author(s):

Marion Avril ◽

Maria Bernabeu ◽

Maxwell Benjamin ◽

Andrew Jay Brazier ◽

Joseph D. Smith

Keyword(s):

Endothelial Cells ◽

Cerebral Malaria ◽

Intercellular Adhesion Molecule ◽

Brain Endothelial Cells ◽

Endothelial Protein C Receptor ◽

Intercellular Adhesion Molecule 1 ◽

Cd36 Expression ◽

Tnf Α ◽

Group A ◽

The Brain

ABSTRACT Intercellular adhesion molecule 1 (ICAM-1) and the endothelial protein C receptor (EPCR) are candidate receptors for the deadly complication cerebral malaria. However, it remains unclear if Plasmodium falciparum parasites with dual binding specificity are involved in cytoadhesion or different parasite subpopulations bind in brain microvessels. Here, we investigated this issue by studying different subtypes of ICAM-1-binding parasite lines. We show that two parasite lines expressing domain cassette 13 (DC13) of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family have dual binding specificity for EPCR and ICAM-1 and further mapped ICAM-1 binding to the first DBLβ domain following the PfEMP1 head structure in both proteins. As PfEMP1 head structures have diverged between group A (EPCR binders) and groups B and C (CD36 binders), we also investigated how ICAM-1-binding parasites with different coreceptor binding traits influence P. falciparum -infected erythrocyte binding to endothelial cells. Whereas levels of binding to tumor necrosis factor alpha (TNF-α)-stimulated endothelial cells from the lung and brain by all ICAM-1-binding parasite lines increased, group A (EPCR and ICAM-1) was less dependent than group B (CD36 and ICAM-1) on ICAM-1 upregulation. Furthermore, both group A DC13 parasite lines had higher binding levels to brain endothelial cells (a microvascular niche with limited CD36 expression). This study shows that ICAM-1 is a coreceptor for a subset of EPCR-binding parasites and provides the first evidence of how EPCR and ICAM-1 interact to mediate parasite binding to both resting and TNF-α-activated primary brain and lung endothelial cells. IMPORTANCE Cerebral malaria is a severe neurological complication of P. falciparum infection associated with infected erythrocyte (IE) binding in cerebral vessels. Yet little is known about the mechanisms by which parasites adhere in the brain or other microvascular sites. Here, we studied parasite lines expressing group A DC13-containing PfEMP1 variants, a subset that has previously been shown to have high brain cell- and other endothelial cell-binding activities. We show that DC13-containing PfEMP1 variants have dual EPCR- and ICAM-1-binding activities and that both receptors are involved in parasite adherence to lung and brain endothelial cells. As both EPCR and ICAM-1 are implicated in cerebral malaria, these findings suggest the possibility that parasites with dual binding activities are involved in parasite sequestration to microvascular beds with low CD36 expression, such as the brain, and we urge more research into the multiadhesive properties of PfEMP1 variants.

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Locally Up-regulated Lymphotoxin α, Not Systemic Tumor Necrosis Factor α, Is the Principle Mediator of Murine Cerebral Malaria

Journal of Experimental Medicine ◽

10.1084/jem.20020128 ◽

2002 ◽

Vol 195 (10) ◽

pp. 1371-1377 ◽

Cited By ~ 188

Author(s):

Christian R. Engwerda ◽

Tracey L. Mynott ◽

Sanjeet Sawhney ◽

J. Brian De Souza ◽

Quentin D. Bickle ◽

...

Keyword(s):

Cerebral Malaria ◽

Parasite Burden ◽

Resistant Cell ◽

Intracellular Adhesion Molecule ◽

Tnf Α ◽

Radiation Resistant ◽

Complement Receptor 3 ◽

Factor Α ◽

Lymphotoxin Α

Cerebral malaria (CM) causes death in children and nonimmune adults. TNF-α has been thought to play a key role in the development of CM. In contrast, the role of the related cyto-kine lymphotoxin α (LTα) in CM has been overlooked. Here we show that LTα, not TNFα, is the principal mediator of murine CM. Mice deficient in TNFα (B6.TNFα−/−) were as susceptible to CM caused by Plasmodium berghei (ANKA) as C57BL/6 mice, and died 6 to 8 d after infection after developing neurological signs of CM, associated with perivascular brain hemorrhage. Significantly, the development of CM in B6.TNFα−/− mice was not associated with increased intracellular adhesion molecule (ICAM)-1 expression on cerebral vasculature and the intraluminal accumulation of complement receptor 3 (CR3)-positive leukocytes was moderate. In contrast, mice deficient in LTα (B6.LTα−/−) were completely resistant to CM and died 11 to 14 d after infection with severe anemia and hyperparasitemia. No difference in blood parasite burden was found between C57BL/6, B6.TNFα−/−, and B6.LTα−/− mice at the onset of CM symptoms in the two susceptible strains. In addition, studies in bone marrow (BM) chimeric mice showed the persistence of cerebral LTα mRNA after irradiation and engraftment of LTα-deficient BM, indicating that LTα originated from a radiation-resistant cell population.

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TNF-α GENE (308G/A) PROMOTER REGION POLYMORPHISM IN METABOLIC SYNDROME: A PILOT STUDY IN NORTH INDIA.

International Journal of Advanced Research ◽

10.21474/ijar01/6062 ◽

2017 ◽

Vol 5 (12) ◽

pp. 1099-1105

Author(s):

SandhyaLal MD ◽

◽

RajniDawar MD ◽

MKBhatnagar MD ◽

JayashreeBhattacharjee MD ◽

...

Keyword(s):

Metabolic Syndrome ◽

Pilot Study ◽

Promoter Region ◽

North India ◽

Tnf Α

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CD47 blockade reduces the pathologic features of experimental cerebral malaria and promotes survival of hosts with Plasmodium infection

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1907653118 ◽

2021 ◽

Vol 118 (11) ◽

pp. e1907653118

Author(s):

Laughing Bear Torrez Dulgeroff ◽

Miranda S. Oakley ◽

Michal C. Tal ◽

Ying Ying Yiu ◽

Joy Q. He ◽

...

Keyword(s):

Cerebral Malaria ◽

Therapeutic Benefit ◽

Plasmodium Yoelii ◽

Experimental Cerebral Malaria ◽

Clinical Syndromes ◽

Pathologic Features ◽

Tnf Α ◽

Infected Rbcs ◽

Circulating Levels

CD47 is an antiphagocytic “don’t eat me” signal that inhibits programmed cell removal of self. As red blood cells (RBCs) age they lose CD47 expression and become susceptible to programmed cell removal by macrophages. CD47−/− mice infected with Plasmodium yoelii, which exhibits an age-based preference for young RBCs, were previously demonstrated to be highly resistant to malaria infection. Our study sought to test the therapeutic benefit of CD47 blockade on ameliorating the clinical syndromes of experimental cerebral malaria (ECM), using the Plasmodium berghei ANKA (Pb-A) murine model. In vitro we tested the effect of anti-CD47 mAb on Plasmodium-infected RBC phagocytosis and found that anti-CD47 treatment significantly increased clearance of Plasmodium-infected RBCs. Infection of C57BL/6 mice with Pb-A is lethal and mice succumb to the clinical syndromes of CM between days 6 and 10 postinfection. Strikingly, treatment with anti-CD47 resulted in increased survival during the cerebral phase of Pb-A infection. Anti-CD47–treated mice had increased lymphocyte counts in the peripheral blood and increased circulating levels of IFN-γ, TNF-α, and IL-22. Despite increased circulating levels of inflammatory cytokines, anti-CD47–treated mice had reduced pathological features in the brain. Survival of ECM in anti-CD47–treated mice was correlated with reduced cellular accumulation in the cerebral vasculature, improved blood–brain barrier integrity, and reduced cytotoxic activity of infiltrating CD8+ T cells. These results demonstrate the therapeutic benefit of anti-CD47 to reduce morbidity in a lethal model of ECM, which may have implications for preventing mortality in young African children who are the highest casualties of CM.

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