Intracellular tumour necrosis factor receptor-2 (TNFR2) signalling. Binding of tumour necrosis factor (TNF) to TNFR2 results in activation and recruitment of intracellular adaptor proteins that induce signal transduction promoting cell proliferation and survival via phosphorylation of endothelial/epithelial nonreceptor tyrosine kinase (Etkp40), which in turn transactivates vascular endothelial growth factor receptor-2 (VEGFR2p1054–1059), leading to phosphatidylinositol 3-kinase (PI3K)-Akt/PKB pathway.
This discovery could lead to new treatment options for the 65% of individuals with IBD who do not respond or become resistant to anti-TNF medications. According to Shivesh Punit of The Saban Research Institute, discovering that tumor necrosis factor receptor 2 (TNFR2) mitigates inflammation in mice was surprising, given that therapies that target tumor necrosis factor (TNF) are the primary treatments for individuals with IBD.
An autoimmune disorder that causes inflammation of the intestinal tract, IBD covers both ulcerative colitis and Crohn’s disease. In the US, >1 million people are living with IBD with a cost of treatment of >1 billion dollars each year. Currently, there is no cure for IBD. For patients with moderate to severe disease, one current therapy acts to blocks TNF. Although anti-TNF medications represent a significant breakthrough in treatment, they are effective in only 1/3 of individuals suffering from IBD. Recent research suggests there are various conditions that lead to the disease including a microbial imbalance in the gut, dysregulated immunity and alterations in the epithelial cells that line the intestinal tract.
They examined the role of TNFR2 in mice with IBD. Biological activity of TNF is mediated by 2 cell surface receptors – TNFR1 and TNFR2. TNFR2 is located primarily on immune cells and during inflammation increases in the intestinal epithelial cells. When they blocked this receptor-mimicking the effect of anti-TNF treatment-they noted an increase in severity and decrease in time to onset of colitis. To verify that the effect was mediated by TNFR2, they did bone marrow transfers, and the mice that got TNFR2-deficient bone marrow developed severe disease.
They also noted loss of TNFR2 increased cytotoxic CD8 T-cells two-fold. When they specifically inhibited CD8 cells, IBD resolved. They also showed that loss of TNFR2 on CD8 cells alone worsened IBD. These observations led the investigators to conclude that CD8 T-cells worsen IBD in this model, and that TNFR2 alleviates IBD by inhibiting these cells. http://www.newswise.com/articles/tumor-necrosis-factor-in-colitis-bad-actor-or-hero
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