LIGHT/TNFSF14 is increased in patients with type 2 diabetes mellitus and promotes islet cell dysfunction and endothelial cell inflammation in vitro

Halvorsen, Bente; Santilli, Francesca; Scholz, Hanne; Sahraoui, Afaf; Gulseth, Hanne Løvdal; Wium, Cecilie; Lattanzio, Stefano; Formoso, Gloria; Fulvio, Patrizia Di; Otterdal, Kari; Retterstøl, Kjetil; Holven, Kirsten B.; Gregersen, Ida; Stavik, Benedicte; Bjerkeli, Vigdis; Michelsen, Annika E.; Ueland, Thor; Liani, Rossella; Davı̀, Giovanni; Aukrust, Pål

doi:10.1007/s00125-016-4036-y

Cited by 52 publications

(57 citation statements)

References 27 publications

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“…results suggested that JAK2/STAT3 activation was involved in HG-stimulated injury in HUVEcs. In addition, as it has been demonstrated that hyperglycemia is involved in vascular endothelium inflammation in vitro and in vivo (29,(40)(41)(42)(43), the present study further examined the role of JAK2/STAT3 activation on the HG-induced inflammatory response in HUVECs. Similar to the results of previous studies (29,(40)(41)(42)(43), it was found that exposure of the HUVECs to HG promoted inflammatory responses, as indicated by the upregulated production of IL-1β, IL-6, IL-12 and TNF-α.…”

Section: Discussionmentioning

confidence: 98%

Ang-(1-7) protects HUVECs from high glucose-induced injury and inflammation via inhibition of the JAK2/STAT3 pathway

Chen

Zhang

et al. 2018

Int J Mol Med

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Angiotensin (Ang)‑1‑7, which is catalyzed by angiotensin‑converting enzyme 2 (ACE2) from angiotensin‑II (Ang‑II), exerts multiple biological and pharmacological effects, including cardioprotective effects and endothelial protection. The Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway has been demonstrated to be involved in diabetes‑associated cardiovascular complications. The present study hypothesized that Ang‑(1‑7) protects against high glucose (HG)‑induced endothelial cell injury and inflammation by inhibiting the JAK2/STAT3 pathway in human umbilical vein endothelial cells (HUVECs). HUVECs were treated with 40 mmol/l glucose (HG) for 24 h to establish a model of HG‑induced endothelial cell injury and inflammation. Protein expression levels of p‑JAK2, t‑JAK2, p‑STAT3, t‑STAT3, NOX‑4, eNOS and cleaved caspase‑3 were tested by western blotting. CCK‑8 assay was performed to assess cell viability of HUVECs. Apoptotic cell death was analyzed by Hoechst 33258 staining. Mitochondrial membrane potential (MMP) was obtained using JC‑1. Superoxide dismutase (SOD) activity was tested by SOD assay kit. Interleukin (IL)‑1β, IL‑10, IL‑12 and TNF‑α levels in culture media were tested by ELISA. The findings demonstrated that exposure of HUVECs to HG for 24 h induced injury and inflammation. This injury and inflammation were significantly ameliorated by pre‑treatment of cells with either Ang‑(1‑7) or AG490, an inhibitor of the JAK2/STAT3 pathway, prior to exposure of the cells to HG. Exposure of the cells to HG also increased the phosphorylation of JAK2/STAT3 (p‑JAK2 and p‑STAT3). Increased activation of the JAK2/STAT3 pathway was attenuated by pre‑treatment with Ang‑(1‑7). To the best of our knowledge, the findings from the present study provided the first evidence that Ang‑(1‑7) protects against HG‑induced injury and inflammation by inhibiting activation of the JAK2/STAT3 pathway in HUVECs.

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Section: Discussionmentioning

confidence: 98%

Ang-(1-7) protects HUVECs from high glucose-induced injury and inflammation via inhibition of the JAK2/STAT3 pathway

Chen

Zhang

et al. 2018

Int J Mol Med

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“…When binding with its receptors herpesvirus entry mediator (HVEM), lymphotoxin b receptor (LTbR), or decoy receptor-3 (in human), LIGHT becomes a T-cell costimulator and can regulate inflammation and tissue homeostasis (16)(17)(18)(19). Recent studies have shown that LIGHT correlates positively with body mass index in obese subjects, which suggests that it is involved in human obesity and metabolic disorders, whereas the exact role of LIGHT in these disorders remains largely unknown (20,21). Lossof-function studies have shown conflicting data.…”

mentioning

confidence: 99%

LIGHT/TNFSF14 signaling attenuates beige fat biogenesis

Kou

Liu

et al. 2018

FASEB j.

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The physiologic signals that regulate beige adipogenesis remain incompletely understood, especially those that limit browning and prevent overexpenditure of energy. In this study, the TNF family member cytokine lymphotoxin-like inducible protein that competes with glycoprotein D for herpesvirus entry on T cells (LIGHT), also known as TNF super family protein 14 (TNFSF14), can inhibit adipose precursor differentiation into beige adipocytes. In acute cold stress, LIGHT deficiency in mice accelerated browning in the subcutaneous white adipose tissue (scWAT). Further experiments showed that LIGHT interacting with lymphotoxin-β receptor (LTβR) on adipose precursors blocked beige fat biogenesis. LTβR signals attenuated the JNK pathway, which contributed to their antibeiging effect. Blocking JNK activation using a small molecular inhibitor prevented cold-induced scWAT beiging. Furthermore, LIGHT/LTβR signals acted as an attenuator of white adipogenesis. LIGHT deficiency in mice promoted obesity during high-fat diet feeding. These findings identify the LIGHT axis as a regulator of adipose tissue homeostasis and suggest that LIGHT signaling functions as a mechanism to divert energy in favor of immune activation.-Kou, Y., Liu, Q., Liu, W., Sun, H., Liang, M., Kong, F., Zhang, B., Wei, Y., Liu, Z., Wang, Y. LIGHT/TNFSF14 signaling attenuates beige fat biogenesis.

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“…1, see below) and/or cytokine-mediated induction of non-canonical ligands. In line with this, β-cells express both the CD40 and lymphotoxin β (LTβR) receptors (Walter et al 2000, Barbe-Tuana et al 2006, Halvorsen et al 2016 and inflammatory cytokines increase the release of LIGHT and upregulate the levels of its receptor (LTβR) in human pancreatic islet cells (Halvorsen et al 2016).…”

Section: Non-canonical Nf-κb Pathway On Glucose Homeostasis and β-Celmentioning

confidence: 80%

“…Moreover, knocking down FBW7 increased the non-canonical NF-κB signaling and apoptosis in both rat and human β-cells exposed to IL-1β + IFN-γ (Meyerovich et al 2016a). Finally, it was previously shown that exposure of human islets to LIGHT (a ligand for the LTβR receptor) induced cell death (Halvorsen et al 2016). These results suggest that activation of the non-canonical pathway is deleterious to β-cells.…”

Section: Non-canonical Nf-κb Pathway On Glucose Homeostasis and β-Celmentioning

confidence: 81%

The non-canonical NF-κB pathway and its contribution to β-cell failure in diabetes

Meyerovich

Ortis

Cardozo

2018

Journal of Molecular Endocrinology

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The prevalence of diabetes has reached 8.8% in worldwide population and is predicted to increase up to 10.4% by 2040. Thus, there is an urgent need for the development of means to treat or prevent this major disease. Due to its role in inflammatory responses, several studies demonstrated the importance of the transcription factor nuclear factor-κB (NF-κB) in both type 1 diabetes (T1D) and type 2 diabetes (T2D). The two major NF-κB pathways are the canonical and the non-canonical. The later pathway is activated by the NF-κB-inducing kinase (NIK) that triggers p100 processing into p52, which forms with RelB its main dimer. Cytokines mediating the activation of this pathway are present in the serum of T1D and T2D patients. Conversely, limited information is available regarding the role of the alternative pathway on diabetes development and β-cell fate. In the present review, we will briefly describe the involvement of NF-κB on diabetes pathology and discuss new studies indicating an important role for the non-canonical NF-κB activation in β-cell function and survival. The non-canonical NF-κB pathway is emerging as a novel potential target for the development of therapeutic strategies to treat or prevent diabetes.

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LIGHT/TNFSF14 is increased in patients with type 2 diabetes mellitus and promotes islet cell dysfunction and endothelial cell inflammation in vitro

Cited by 52 publications

References 27 publications

Ang-(1-7) protects HUVECs from high glucose-induced injury and inflammation via inhibition of the JAK2/STAT3 pathway

Ang-(1-7) protects HUVECs from high glucose-induced injury and inflammation via inhibition of the JAK2/STAT3 pathway

LIGHT/TNFSF14 signaling attenuates beige fat biogenesis

The non-canonical NF-κB pathway and its contribution to β-cell failure in diabetes

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