Dataset Information

Membrane lymphotoxin-α₂β is a novel tumor necrosis factor (TNF) receptor 2 (TNFR2) agonist.

ABSTRACT: In the early 1990s, it has been described that LTα and LTβ form LTα₂β and LTαβ₂ heterotrimers, which bind to TNFR1 and LTβR, respectively. Afterwards, the LTαβ₂-LTβR system has been intensively studied while the LTα₂β-TNFR1 interaction has been ignored to date, presumably due to the fact that at the time of identification of the LTα₂β-TNFR1 interaction one knew already two ligands for TNFR1, namely TNF and LTα. Here, we show that LTα₂β interacts not only with TNFR1 but also with TNFR2. We furthermore demonstrate that membrane-bound LTα₂β (memLTα₂β), despite its asymmetric structure, stimulates TNFR1 and TNFR2 signaling. Not surprising in view of its ability to interact with TNFR2, LTα₂β is inhibited by Etanercept, which is approved for the treatment of rheumatoid arthritis and also inhibits TNF and LTα.

SUBMITTER: Kucka K

PROVIDER: S-EPMC8024344 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Publications

Membrane lymphotoxin-α2β is a novel tumor necrosis factor (TNF) receptor 2 (TNFR2) agonist.

Kucka Kirstin K Lang Isabell I Zhang Tengyu T Siegmund Daniela D Medler Juliane J Wajant Harald H

Cell death & disease 20210406 4

In the early 1990s, it has been described that LTα and LTβ form LTα2β and LTαβ2 heterotrimers, which bind to TNFR1 and LTβR, respectively. Afterwards, the LTαβ2-LTβR system has been intensively studied while the LTα2β-TNFR1 interaction has been ignored to date, presumably due to the fact that at the time of identification of the LTα2β-TNFR1 interaction one knew already two ligands for TNFR1, namely TNF and LTα. Here, we show that LTα2</ ...[more]

PMID: 33824270

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Project description:To investigate the significance of functional polymorphisms of inflammatory response genes by analysis of a large population of patients, both with and without severe sepsis, and representative of the diverse populations (geographic diversity, physician diversity, clinical treatment diversity) that would be encountered in critical care clinical practice.: Collaborative case-control study conducted from July 2001 to December 2005.A heterogeneous population of patients from 12 U.S. intensive care units represented by the Genetic Predisposition to Severe Sepsis archive.A total of 854 patients with severe sepsis and an equal number of mortality, age, gender, and race-matched patients also admitted to the intensive care unit without evidence of any infection (matched nonseptic controls).We developed assays for six functional single nucleotide polymorphisms present before the first codon of tumor necrosis factor at -308, IL1B at -511, IL6 at -174, IL10 at -819, and CD14 at -159, and in the first intron of LTA (also known as tumor necrosis factor-B) at +252 (LTA[+252]). The Project IMPACT critical care clinical database information management system developed by the Society of Critical Care Medicine and managed by Tri-Analytics and Cerner Corporation was utilized. Template-directed dye-terminator incorporation assay with fluorescence polarization detection was used as a high-throughput genotyping strategy. Fifty-three percent of the patients were male with 87.3% and 6.4% of Caucasian and African American racial types, respectively. Overall mortality was 35.1% in both severe sepsis and matched nonseptic control patients group. Average ages (standard deviation) of the severe sepsis and matched nonseptic control patients were 63.0 (16.05) and 65.0 (15.58) yrs old, respectively. Among the six single nucleotide polymorphisms, LTA (+252) was most overrepresented in the septic patient group (% severe sepsis; AA 45.6: AG 51.1: GG 56.7, p = .005). Furthermore, the genetic risk effect was most pronounced in males, age >60 yrs (p = .005).LTA(+252) may influence predisposition to severe sepsis, a predisposition that is modulated by gender and age. Although the genetic influences can be overwhelmed by both comorbid factors and acute illness in individual cases, population studies suggest that this is an influential biological pathway modulating risk of critical illnesses.

Dataset Information

Membrane lymphotoxin-α₂β is a novel tumor necrosis factor (TNF) receptor 2 (TNFR2) agonist.

Publications

Membrane lymphotoxin-α<sub>2</sub>β is a novel tumor necrosis factor (TNF) receptor 2 (TNFR2) agonist.

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