TNF Gene (Tumor Necrosis Factor Alpha): Function, Mutations, and Disease Associations

The TNF gene encodes tumor necrosis factor-alpha (TNF-α), a multifunctional proinflammatory cytokine belonging to the tumor necrosis factor superfamily. It is primarily produced by activated macrophages, lymphocytes, and other immune cells. TNF-α exists as a transmembrane protein that is cleaved by ADAM17 to release a soluble form. It signals through TNF receptors (TNFR1 and TNFR2) to regulate inflammation, immune responses, apoptosis, and cell proliferation. Dysregulation of TNF is implicated in autoimmune diseases, cancer, and infectious diseases.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• TNF signaling pathway (KEGG hsa04668)

• Cytokine-cytokine receptor interaction (KEGG hsa04060)

• Apoptosis (KEGG hsa04210)

• NF-kappa B signaling pathway (KEGG hsa04064)

• Inflammatory bowel disease (KEGG hsa05321)

TNF-α is a 233-amino acid type II transmembrane protein (26 kDa) that is cleaved by ADAM17 to produce a soluble 17 kDa form. It forms homotrimers and binds to two receptors: TNFR1 (TNFRSF1A) and TNFR2 (TNFRSF1B). TNFR1 is widely expressed and mediates most proinflammatory and apoptotic signals via TRADD and RIPK1, leading to NF-κB activation or caspase-dependent apoptosis. TNFR2 is mainly found on immune cells and promotes cell survival and proliferation. TNF-α is a key therapeutic target; monoclonal antibodies (e.g., infliximab, adalimumab) and soluble receptor fusion proteins (etanercept) are used to treat autoimmune diseases.