The tumor necrosis factor (TNF) superfamily of cytokines represents a multifunctional group of pro-inflammatory cytokines which activate signaling pathways for cell survival, apoptosis, inflammatory responses, and cellular differentiation. Induction of cellular responses to tumor necrosis factor occurs through two receptors, TNFR1 (TNF Receptor-1 or CD120a) and TNFR2 (TNF Receptor-2 or CD120b). TNFR1 is activated in most human tissues by the binding of TNFα. TNFR2 is expressed in immune cells and is activated by both TNFα and TNFβ . Thermo Scientific™ has a wide range of products to help with TNF research.
Key TNF Pathway Targets
TNF interacts with many pathway targets, including:
In response to inflammation and infection, the pro-inflammatory cytokine TNFα is produced by macrophages, lymphocytes, fibroblasts and keratinocytes. TNFα elicits its pro-inflammatory signals by initially binding to receptors, TNFR1 (p55) and TNFR2 (p75), on the cell surface. TNFR1 and TNFR2 elicit cellular responses to TNFα via three distinct signaling pathways leading to the activation of caspases and the activation of AP-1 and NFκB transcription factors . Activation by TNFα results in the trimerization of the TNFR1 receptor and association of death domains located on the cytoplasmic region of the TNFR1 protein.
Aggregation of the death domains leads to the recruitment of the TRADD (TNFR-Associated Death Domain) adaptor proteins. Additional TRADD mediated recruitment of FADD (Fas-Associated Death Domain), RAIDD (RIP-Associated ICH-1/CED-3-homologous protein with a Death Domain), MADD (MAPK Activating Death Domain) and RIP (Receptor-Interacting Protein) results in the activation of caspase 8. Caspase 8 mediates a series of regulated protein cleavage events that ultimately results in apoptosis.
Cleavage of BID (BH3 interacting death domain) by caspase 8 generates tBID (truncated BID) resulting in the disruption of the mitochondrial membrane and the release of cytochrome c (CytoC). Binding of CytoC to APAF1 (apoptotic protease activating factor-1), allows recruitment of caspase 9 which cleaves caspase 3 creating its active form. The activation of caspases at this stage of the signaling pathway can be inhibited by XIAP (X-linked inhibitor of apoptosis).
Activation of the transcription factors AP-1 and NFκB via TNF signaling is mediated by the association of TRAF2 (TNF Receptor-Associated Factor-2) with TRADD, thereby creating a fully activated complex with MADD, and RIP. Translocation of NFκB to the nucleus occurs when this complex phosphorylates IκK following association with NIK (NF-κB-inducing kinase), resulting in the degradation of IκB . Activation of the AP-1 transcriptional complexes occurs via the activation MAPKs by the TNFR1, TRADD, TRAF2, MADD, RIP complex (Jun NH2-terminal kinase). AP-1 is required for the transcriptional activation of many stress and growth related genes .
Thermo Scientific™ offers antibodies, ELISAs, Luminex® multiplex assays and growth factors for key targets in the TNF signaling pathway.
Featured below is ELISA and flow cytometry data using Thermo Scientific™ products.
- Kawasaki H. et al. (2002) Identification of genes that function in the TNFα-mediated apoptotic pathway using randomized hybrid ribozyme libraries. Nat Biotechnol 20: 376-80.
- Kagoya, Y. et al. (2014) Positive feedback between NF-κB and TNF-α promotes leukemia-initiating cell capacity. J Clin Invest 124(2): 528-542.
- Baud V. et al. (2001) Signal transduction by tumor necrosis factor and its relatives. Trends Cell Biol 11: 372-7.
- Kai-Li He. et al. (2002) A20 Inhibits Tumor necrosis factor (TNF) α-Induced apoptosis by disrupting recruitment of TRADD and RIP to the TNF receptor 1 complex in jurkat T cells. Mol Cell Biol 22: 6034-6045.
|Product Name||Catalog Number|
|Cytochrome C Antibody||456100|
|Caspase 3 Antibody||PA516335|