Gene polymorphism at position −308 of the tumor-necrosis -factor-α (TNF-α) in Multiple Sclerosis and it's influence on the regulation of TNF-α production

Tumor necrosis factor α (TNF-α) plays a central role in the pathophysiology of Alzheimer’s disease (AD). Food and Drug Administration–approved biologic TNF-α inhibitors are thus a potential treatment for AD, but they do not cross the blood-brain barrier. In this short review, we discuss the involvement of TNF-α in AD, challenges associated with the development of existing biologic TNF-α inhibitors for AD, and potential therapeutic strategies for targeting TNF-α for AD therapy.

Download Full-text

Tumor necrosis factor-α-associated lysosomal permeabilization is cathepsin B dependent

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00151.2002 ◽

2002 ◽

Vol 283 (4) ◽

pp. G947-G956 ◽

Cited By ~ 113

Author(s):

Nathan W. Werneburg ◽

M. Eugenia Guicciardi ◽

Steven F. Bronk ◽

Gregory J. Gores

Keyword(s):

Tumor Necrosis Factor ◽

Cathepsin B ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

Fluorescent Protein ◽

Tnf Α ◽

Calcein Release ◽

Green Fluorescent ◽

Factor Α ◽

Necrosis Factor

Cathepsin B (Cat B) is released from lysososomes during tumor necrosis factor-α (TNF-α) cytotoxic signaling in hepatocytes and contributes to cell death. Sphingosine has recently been implicated in lysosomal permeabilization and is increased in the liver by TNF-α. Thus the aims of this study were to examine the mechanisms involved in TNF-α-associated lysosomal permeabilization, especially the role of sphingosine. Confocal microscopy demonstrated Cat B-green fluorescent protein and LysoTracker Red were both released from lysosomes after treatment of McNtcp.24 cells with TNF-α/actinomycin D, a finding compatible with lysosomal destabilization. In contrast, endosomes labeled with Texas Red dextran remained intact, suggesting lysosomes were specifically targeted for permeabilization. LysoTracker Red was released from lysosomes in hepatocytes treated with TNF-α or sphingosine in Cat B(+/+) but not Cat B(−/−) hepatocytes, as assessed by a fluorescence-based assay. With the use of a calcein release assay in isolated lysosomes, sphingosine permeabilized liver lysosomes isolated from Cat B(+/+) but not Cat B(−/−) liver. C6ceramide did not permeabilize lysosomes. In conclusion, these data implicate a sphingosine-Cat B interaction inducing lysosomal destabilization during TNF-α cytotoxic signaling.

Download Full-text

Prolyl Hydroxylase 3 (PHD3) Modulates Catabolic Effects of Tumor Necrosis Factor-α (TNF-α) on Cells of the Nucleus Pulposus through Co-activation of Nuclear Factor κB (NF-κB)/p65 Signaling

Journal of Biological Chemistry ◽

10.1074/jbc.m112.375964 ◽

2012 ◽

Vol 287 (47) ◽

pp. 39942-39953 ◽

Cited By ~ 51

Author(s):

Nobuyuki Fujita ◽

Shilpa S. Gogate ◽

Kazuhiro Chiba ◽

Yoshiaki Toyama ◽

Irving M. Shapiro ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Nucleus Pulposus ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

Nuclear Factor Κb ◽

Nuclear Factor ◽

Co Activation ◽

Tnf Α ◽

Factor Α ◽

Necrosis Factor

Download Full-text

Tumor Necrosis Factor-α −308 Genotypes Influence Inflammatory Activity and TNF-α Serum Concentrations in Children with Juvenile Idiopathic Arthritis

The Journal of Rheumatology ◽

10.3899/jrheum.080615 ◽

2009 ◽

Vol 36 (4) ◽

pp. 837-842 ◽

Cited By ~ 18

Author(s):

ANA FILIPA MOURÃO ◽

JOANA CAETANO-LOPES ◽

PAULA COSTA ◽

HELENA CANHÃO ◽

MARIA JOSÉ SANTOS ◽

...

Keyword(s):

Juvenile Idiopathic Arthritis ◽

Tumor Necrosis Factor ◽

Disease Activity ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

Inflammatory Activity ◽

Serum Concentrations ◽

Tnf Α ◽

Factor Α ◽

Necrosis Factor

Objective.Considering the relevance of tumor necrosis factor-α (TNF-α) in the pathophysiology of juvenile idiopathic arthritis (JIA), it is likely that polymorphisms in its promoter area may be relevant in disease susceptibility and activity. We investigated if clinical measures of JIA activity and TNF-α serum concentrations were associated with TNF-α −308 genotypes.Methods.Portuguese patients with JIA in 5 pediatric rheumatology centers were recruited consecutively, along with a control group of healthy subjects. Demographic and clinical data and blood samples were collected from each patient. DNA was extracted for analysis of TNF-α gene promoter polymorphisms at position −308 by restriction fragment-length polymorphism.Results.One hundred fourteen patients and 117 controls were evaluated; 57% of patients presented the oligoarticular subtype, 25% the polyarticular subtype, 8% the systemic subtype, and 9% had enthesitis-related arthritis and 5% psoriatic arthritis. Twenty-four percent of the patients presented the −308 GA/AA genotypes and 76% the −308 GG genotype, similar to findings in controls. Patients with the −308 GA/AA genotype had higher degree of functional impairment, erythrocyte sedimentation rate, 100-mm visual analog scale score for disease activity, and TNF-α levels compared to those with the −308 GG genotype.Conclusion.TNF-α −308 GA/AA genotypes were found to be related to higher inflammatory activity and worse measures of disease activity in Portuguese patients with JIA. They were not associated with susceptibility to JIA.

Download Full-text