Tumor necrosis factor (TNF)-alpha is a pro-inflammatory cytokine belonging to the TNF superfamily that is secreted by monocytes/macrophages, T cell, and natural killer (NK), among others (1). TNF-alpha is synthesized as a 233 amino acid (aa) transmembrane protein (mTNF-alpha) with a theoretical molecular weight (MW) of 26 kDa (1,2) that forms a homotrimer. mTNF-alpha is cleaved by TNF-alpha converting enzyme (TACE) and released in its 157 aa, 17 kDa soluble form (sTNF-alpha) (1-5). Both mTNF-alpha and sTNF-alpha are capable of binding type 1 TNF receptors (TNFR1), whereas mTNF-alpha predominately binds to TNFR2 (1,2). TNF-alpha binding to its receptors causes receptor recruitment of adaptor proteins, formation of signaling complexes, and downstream signaling cascades (e.g. MAPK, NF-kappaB, and Caspase-8), leading to distinct cellular responses such as survival, proliferation, inflammation, necroptosis, and apoptosis (1-5).
TNF-alpha is critical for normal immune response; however, dysregulation of TNF-alpha production can result in various pathologies (2,4,5). Excessive production of pro-inflammatory cytokines including interleukin 1 (IL-1), IL-6, and TNF-alpha has been implicated in an array of autoimmune diseases like rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis (2,4,5). Anti-TNF monoclonal antibodies, including Infliximab, and soluble TNFR have been approved for the treatment of autoimmune and TNF-mediated diseases (5). Additionally, data suggests that TNF inhibitors can be beneficial for treating patients experiencing immune-related adverse events associated with immune checkpoint inhibitor cancer treatment (6).
References
1. Holbrook J, Lara-Reyna S, Jarosz-Griffiths H, McDermott M. Tumour necrosis factor signalling in health and disease. F1000Res. 2019;8:F1000 Faculty Rev-111. https://doi.org/10.12688/f1000research.17023.1
2. Jang DI, Lee AH, Shin HY, et al. The Role of Tumor Necrosis Factor Alpha (TNF-alpha) in Autoimmune Disease and Current TNF-alpha Inhibitors in Therapeutics. Int J Mol Sci. 2021;22(5):2719. https://doi.org/10.3390/ijms22052719
3. Horiuchi T, Mitoma H, Harashima S, Tsukamoto H, Shimoda T. Transmembrane TNF-alpha: structure, function and interaction with anti-TNF agents. Rheumatology (Oxford). 2010;49(7):1215-1228. https://doi.org/10.1093/rheumatology/keq031
4. Webster JD, Vucic D. The Balance of TNF Mediated Pathways Regulates Inflammatory Cell Death Signaling in Healthy and Diseased Tissues. Front Cell Dev Biol. 2020;8:365. https://doi.org/10.3389/fcell.2020.00365
5. Kalliolias GD, Ivashkiv LB. TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nat Rev Rheumatol. 2016; 12(1):49-62. https://doi.org/10.1038/nrrheum.2015.169
6. Chen AY, Wolchok JD, Bass AR. TNF in the era of immune checkpoint inhibitors: friend or foe?. Nat Rev Rheumatol. 2021;17(4):213-223. doi:10.1038/s41584-021-00584-4
