Expression of TWEAK and its receptor Fn14 in human subcutaneous adipose tissue. Relationship with other inflammatory cytokines in obesity

Chacón, Matilde R.; Richart, C; Gómez, José Manuel; Megía, Ana; Vilarrasa, Núria; Fernández-Real, José Manuel; Garcı́a-España, Antonio; Miranda, Merce; Masdevall, Carlos; Ricard, W; Caubet, Enric; Soler, Juan; Vendrell, Joan

doi:10.1016/j.cyto.2005.12.005

Cited by 45 publications

(44 citation statements)

References 26 publications

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“…In an alternative study, TWEAK mRNA expression levels were not significantly different between lean and obese subjects. However, TWEAK receptor expression was only quantifiable in subjects with a BMI of >38 kg/m 2 (38). In the present study, no significant difference in the serum TWEAK expression levels was identified between obese control and BC patients.…”

Section: Discussionmentioning

confidence: 47%

Increased serum tumor necrosis factor receptor-associated factor-6 expression in patients with non-metastatic triple-negative breast cancer

et al. 2015

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Abstract. Obesity appears to be associated with an increased risk of breast cancer (BC) and an inferior oncological outcome at the time of diagnosis, with poor outcomes most prominent in cases of triple-negative BC (TNBC). The present study analyzed serum tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and TNF receptor associated factor-6 (TRAF) protein expression levels in 48 patients with non-metastatic BC and 26 obese control patients (without BC). The mean age of the cohort was 52.5 years (range, 35-78 years) and the patients had a median body mass index of 33.5 kg/m 2 (range, 30-47 kg/m 2 ). In the study population, 27.1% of BC patients were triple negative and 70.8% were hormone receptor (HR)-positive. Median serum TRAF6 expression was 0.90 ng/ml (range, 0.55-1.53 ng/ml) in the 13 TNBC patients and 0.63 ng/ml (range, 0.49-1.22 ng/ml) in the 35 HR-positive BC patients; thus, TRAF6 expression was significantly higher in the TNBC patients compared with the obese control group (0.90 vs. 0.73 ng/ml; P=0.033). Furthermore, median serum TRAF6 expression levels were significantly higher in HR-negative patients compared with HR-positive patients (0.83 vs. 0.62 ng/ml; P=0.002). The present study demonstrated that serum TRAF6 expression levels were increased in TNBC and HR-negative patients with non-metastatic BC compared with HR-and human epidermal growth factor receptor 2-positive cases or the obese healthy control group. Therefore, elevated TRAF6 expression may be a poor prognostic factor in non-metastatic BC. In addition, we propose that progesterone (PR) negativity may be a more useful poor prognosis factor than estrogen receptor (ER) negativity, as TRAF6 expression levels were higher in the PR-negative patients compared with the ER-negative patients.

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Section: Discussionmentioning

confidence: 47%

Increased serum tumor necrosis factor receptor-associated factor-6 expression in patients with non-metastatic triple-negative breast cancer

et al. 2015

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Section: Tweak Gene Expressionmentioning

confidence: 99%

“…Indeed, TWEAK mRNA and/or protein expression has been detected in many different tissues 4,5,19,[22][23][24][25] and tumour specimens 20,23,26,27 . TWEAK is also expressed in primary murine neurons 28 and astrocytes 28,29 , in monocytes/ macrophages 4,21,22,30,31 and in various human tumour cell lines 4,5,20,26, 27.…”

Section: Tweak Gene Expressionmentioning

confidence: 99%

“…It has been reported that IFN-γ30 , 32 or phorbol myristate acetate 30 treatment of human primary monocytes can increase TWEAK levels, as determined by fluorescence-activated cell-sorter analysis. Also, lipopolysaccharide (LPS) treatment of human THP-1 monocytic cells induces TWEAK mRNA expression 25 ; curiously, LPS treatment of murine peritoneal macrophages has the opposite effect 22 . Finally, TWEAK expression is upregulated in three murine models of acute injury; specifically, in the brain after focal cerebral ischaemia 28,33 , in the kidney after intraperitoneal injection of folic acid 34 and in skeletal muscle after cardiotoxin injection 31 .…”

Section: Tweak Gene Expressionmentioning

confidence: 99%

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The TWEAK–Fn14 cytokine–receptor axis: discovery, biology and therapeutic targeting

Winkles

2008

Nat Rev Drug Discov

524

662

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TWEAK is a multifunctional cytokine that controls many cellular activities including proliferation, migration, differentiation, apoptosis, angiogenesis and inflammation. TWEAK acts by binding to Fn14, a highly inducible cell-surface receptor that is linked to several intracellular signalling pathways, including the nuclear factor-κB (NF-κB) pathway. The TWEAK-Fn14 axis normally regulates various physiological processes, in particular it seems to play an important, beneficial role in tissue repair following acute injury. Furthermore, recent studies have indicated that TWEAK-Fn14 axis signalling may contribute to cancer, chronic autoimmune diseases and acute ischaemic stroke. This Review provides an overview of TWEAK-Fn14 axis biology and summarizes the available data supporting the proposal that both TWEAK and Fn14 should be considered as potential targets for the development of novel therapeutics.Cytokines are a large and diverse group of plasma-membrane-associated or secreted proteins that bind cell-surface receptors and thereby regulate many important biological processes. These processes include development, haematopoesis, inflammation, immune responses and tissue repair1. The tumour necrosis factor (TNF) ligand superfamily, and the receptors that mediate their effects, is a cytokine-receptor subgroup that has attracted considerable interest as a potential source of therapeutic targets for the management of complex human diseases. TNF superfamily ligands are primarily expressed as type II transmembrane proteins, but in some cases they are processed into smaller, secreted proteins that retain biological activity2 , 3. Both the anchored and soluble cytokines contain a C-terminal TNF homology domain that mediates self-trimerization and receptor binding. TNF superfamily members bind to one or more members of the TNF receptor (TNFR) superfamily, most of which are type I or type III transmembrane proteins2 , 3. These receptors are characterized by the presence of an extracellular, ligand-binding region containing one to four cysteine-rich domains and a cytoplasmic tail containing one or more adaptor-protein binding sites. TWEAK (also known as TNFSF12, APO3L, CD255) and its cognate receptor Fn14 (also known as TNFRSF12A, TWEAKR, CD266) are members of the TNF and TNFR superfamilies, respectively, and the discovery of this cytokine-receptor axis was in itself an interesting scientific journey. In 1997, Chicheportiche et al. 4 reported the identification of a novel TNF-like protein that had pro-apoptotic activity on interferon-α (IFN-γ)-treated human HT-29 colon carcinoma cells. Consequently, they named this cytokine TNF-like weak inducer of apoptosis (abbreviated to TWEAK). These investigators were recipients of unexpected good fortune, as they were not originally aiming to identify new TNF superfamily members; indeed, the TWEAK cDNA was cloned during a screen for erythropoietin-related mRNAs in mouse macrophages. In 1998, Marsters et al. 5 reported the identification of the same protein by searching an expre...

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“…However, several lines of evidence also show that sTWEAK may modulate the cellular responses to TNF-␣ by competition at a molecular level for shared limiting factors (29,46). Although TWEAK and its receptor Fn14 are expressed in a variety of organs, including adipose tissue (7), the physiological and patho-physiological roles of this cytokine in an obesity-associated insulin-resistant state remains largely unknown. TWEAK has been described to inhibit adipogenesis (40) and we have recently shown that TWEAK may have a proinflammatory function in human subcutaneous adipocytes (42).…”

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confidence: 99%

TWEAK prevents TNF-α-induced insulin resistance through PP2A activation in human adipocytes

Vázquez-Carballo

Ceperuelo-Mallafré

Chacón

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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Expression of TWEAK and its receptor Fn14 in human subcutaneous adipose tissue. Relationship with other inflammatory cytokines in obesity

Cited by 45 publications

References 26 publications

Increased serum tumor necrosis factor receptor-associated factor-6 expression in patients with non-metastatic triple-negative breast cancer

Increased serum tumor necrosis factor receptor-associated factor-6 expression in patients with non-metastatic triple-negative breast cancer

The TWEAK–Fn14 cytokine–receptor axis: discovery, biology and therapeutic targeting

TWEAK prevents TNF-α-induced insulin resistance through PP2A activation in human adipocytes

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