What is Tumor Necrosis Factor Family?

Tumor necrosis factor (TNF) family, a large family of cytokines that cause apoptosis, plays key roles in inflammation and immunity. TNF family ligands and their corresponding receptors (TNF-Rs) have pivotal roles in many biological processes in mammalian cells, such as in host defence, inflammation, apoptosis, autoimmunity and organogenesis. At least 18 TNF ligands and 28 receptors have been identified so far. Some ligands have multiple receptors, and some receptors also bind multiple ligands. The interactions between ligands and receptors are usually very specific and have high affinity (0.1-1 nM) .

The tumour necrosis factor (TNF) ligand TALL-1 and its cognate receptors, BCMA, TACI and BAFF-R, were recently identified as members of the TNF superfamily, which are essential factors contributing to B-cell maturation. The functional, soluble fragment of TALL-1 (sTALL-1) forms a virus-like assembly for its proper function.

Tumor necrosis factor (TNF) acts on various cell types to coordinate immune and inflammatory responses. Inappropriate production of TNF or sustained activation of TNF signaling has been associated with diverse human disorders including rheumatoid arthritis, inflammatory bowel disease, diabetes and cancer. TNF mediates its effects mainly through the nuclear factor-kB (NF-kB) and mitogen-activated protein kinase (MAPK) signaling pathways, which promote NF-kB and activator protein 1–mediated transcription, respectively. The transcribed genes can promote cellular proliferation, differentiation, inflammation or cell death. Exactly how a cell responds to TNF, whether it survives and proliferates, differentiates or dies, can vary depending on the cell type and the cellular environment. The overall balance in the activation of signaling pathways induced by TNF, particularly that of the MAPK and NF-kB cascades, is a key factor in dictating the nature of the cellular response.

Fig 1 TNF-alpha-induced miR-342 promotes microglia activation through NF-kB and induces neurotoxicity

TNF-α is a member of Tumor Necrosis Factor Family. SPI1 promotes the malignant phenotype of GSCs (Glioma stem cells) via TNF-α mediated NF-κB signaling. SPI1 can also transcriptionally upregulate DGCR8 expression, and the latter can maintain the stability of circKPNB1 and form a positive feedback loop among DGCR8, circKPNB1and SPI1. circKPNB1 was a novel oncogene in GBM and of great significance in the diagnosis and prognosis prediction of GBM (Glioblastoma) and maybe a novel target for molecular targeted therapy.

Fig 2 Schematic diagram showing DGCR8/ circKPNB1/SPI1 feedback loop regulates

glioma tumorigenesis via TNF-mediated NF-κb signaling pathway

Further study of TNFs and their downstream signaling pathways will help to find drug therapeutic targets for many diseases, including diabetes, cancers, etc.