The G-308A variant of the Tumor Necrosis Factor-α (TNF-α) gene is not associated with obesity, insulin resistance and body fat distribution

Objective.Our main objective was to assess the relationship between body composition (BC) and response to tumor necrosis factor-α (TNF-α) blocker treatment in patients with ankylosing spondylitis (AS). Our secondary objective was to evaluate the change of BC after treatment, accounting for sex and age.Methods.All included patients fulfilled the modified New York criteria for AS and were naive to TNF-α blocker. They were followed for at least 6 months after the start of etanercept or adalimumab. The Ankylosing Spondylitis Disease Activity Score containing C-reactive protein (ASDAS-CRP) and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) were reported. BC was assessed by whole body dual-energy X-ray absorptiometry. Body fat percentage (BF%), fat mass index (FMI), and fat free mass index (FFMI) were reported as absolute values and as percentiles.Results.Forty-one patients were included (61% men). The median followup was 14.3 months (interquartile range 8.4–19.4). After multivariate regression analysis, more fat at baseline (BF%, FMI, or FMI percentile) was significantly related with a lower chance of achieving a clinically important improvement of the ASDAS-CRP or BASDAI after treatment. The body composition did not change significantly after treatment, but there was a trend toward muscle recovery in men (FFMI change from 34.0th to 37.4th percentile).Conclusion.Higher body fat content at baseline was independently associated with a worse response to treatment with TNF-α blockers, measured by ASDAS-CRP and BASDAI change, and might contribute to the lower response rates in female patients. Also, there is a trend toward muscle mass recovery in male patients after treatment.

Download Full-text

#50 Gestational exposure of tumor necrosis factor-α (TNF-α) inhibitor drugs

Reproductive Toxicology ◽

10.1016/j.reprotox.2019.05.068 ◽

2019 ◽

Vol 88 ◽

pp. 149-150 ◽

Cited By ~ 1

Author(s):

Erkoseoglu Ilknur ◽

Kadioglu Mine ◽

Cavusoglu Irem ◽

Sisman Mulkiye ◽

Aran Turhan ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

Gestational Exposure ◽

Tnf Α ◽

Factor Α ◽

Necrosis Factor

Download Full-text

Tumor necrosis factor α Inhibition for Alzheimer’s Disease

Journal of Central Nervous System Disease ◽

10.1177/1179573517709278 ◽

2017 ◽

Vol 9 ◽

pp. 117957351770927 ◽

Cited By ~ 43

Author(s):

Rudy Chang ◽

Kei-Lwun Yee ◽

Rachita K Sumbria

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

Short Review ◽

Tnf Α ◽

Factor Α ◽

Ad Therapy ◽

Necrosis Factor

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

Tumor Necrosis Factor α Regulates Responses to Nerve Growth Factor, Promoting Neural Cell Survival but Suppressing Differentiation of Neuroblastoma Cells

Molecular Biology of the Cell ◽

10.1091/mbc.e07-06-0624 ◽

2008 ◽

Vol 19 (3) ◽

pp. 855-864 ◽

Cited By ~ 21

Author(s):

Yoshinori Takei ◽

Ronald Laskey

Keyword(s):

Nerve Growth Factor ◽

Growth Factor ◽

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

Neuroblastoma Cells ◽

Erk Activation ◽

Tnf Α ◽

Factor Α ◽

Necrosis Factor

Although nerve growth factor (NGF) promotes survival of neurons, tumor necrosis factor α (TNF-α) contributes to cell death triggered by NGF depletion, through TNF-α receptor (TNFR) 1. In contrast to this effect, TNF-α can promote neural cell survival via TNF-α receptor TNFR2. Although these findings demonstrate pivotal roles of TNF-α and NGF in cell fate decisions, cross-talk between these signaling pathways has not been clarified. We find that NGF can induce TNF-α synthesis through the nuclear factor-κB transcription factor. This provides a new basis for examining the cross-talk between NGF and TNF-α. Inhibition of TNFR2 shows opposite effects on two downstream kinases of NGF, extracellular signal-regulated kinase (Erk) and Akt. It increases Erk activation by NGF, and this increased activation induces differentiation of neuroblastoma cell lines. Reciprocally, inhibition of TNFR2 decreases Akt activation by NGF. Consistent with an essential role of Akt in survival signaling, inhibition of TNF-α signaling decreases NGF-dependent survival of neurons from rat dorsal root ganglia. Thus, NGF and NGF-induced TNF-α cooperate to activate Akt, promoting survival of normal neural cells. However, the NGF-induced TNF-α suppresses Erk activation by NGF, blocking NGF-induced differentiation of neuroblastoma cells. TNFR2 signaling could be a novel target to modulate cell responses to NGF.

Download Full-text

Interleukin-1 and tumor necrosis factor-α increase insulin-like growth factor-binding protein-3 (IGFBP-3) production and IGFBP-3 protease activity in human articular chondrocytes

Journal of Endocrinology ◽

10.1677/joe.0.1460279 ◽

1995 ◽

Vol 146 (2) ◽

pp. 279-286 ◽

Cited By ~ 49

Author(s):

R C Olney ◽

D M Wilson ◽

M Mohtai ◽

P J Fielder ◽

R L Smith

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

Articular Chondrocytes ◽

Tnf Α ◽

Igf I ◽

Matrix Production ◽

Factor Α ◽

Necrosis Factor ◽

Igfbp 3

Abstract IGF-I is the major anabolic factor for cartilage matrix production. Chondrocytes and cartilage treated with interleukin-1α (IL-1α), and chondrocytes from several models of inflammatory joint disease, exhibit reduced responsiveness to IGF-I. Since the IGF-binding proteins (IGFBPs) modulate the effects of IGF-I, we examined the effect of IL-1α and tumor necrosis factor-α (TNF-α) on IGFBP production by normal human articular chondrocytes in primary culture. Western ligand blots and immunoprecipitation of conditioned medium samples showed that articular chondrocytes produced IGFBPs-2, −3 and −4 and glycosylated IGFBP-4. Both IL-1α and TNF-α increased chondrocyte production of IGFBP-3, but did not alter IGFBP-4 production. The activity of a neutral metalloprotease with the ability to cleave IGFBP-3 was also increased by IL-1α. These data suggest that the cytokines IL-1α and TNF-α may act to reduce IGF-I access to chondrocytes by increasing production of IGFBP-3. This may be a factor in the decreased matrix production in the inflammatory arthritides. Journal of Endocrinology (1995) 146, 279–286

Download Full-text