TNF

Tumor necrosis factor (TNF) is a proinflammatory cytokine that plays a central role in systemic inflammation and in the regulation of immune cells. The TNF system comprises two main ligands: soluble TNF-α, produced mainly by activated macrophages, T cells, and natural killer cells; and lymphotoxin-α (TNF-β), produced by lymphocytes. Membrane-bound TNF can be cleaved to form soluble TNF by the metalloprotease ADAM17 (TACE). The TNF gene (TNF) is located in the human major histocompatibility complex on chromosome 6.

TNF signals via two receptors, TNFR1 (p55) and TNFR2 (p75). TNFR1 is broadly expressed and can initiate apoptosis through TRADD, FADD, and caspases, in addition to activating NF-κB and MAPK pathways. TNFR2 is mainly on immune cells and tends to promote cell activation and survival. The balance of signaling through these receptors shapes the inflammatory response.

TNF regulates leukocyte recruitment, endothelial activation, fever, and acute-phase responses. It also influences tissue remodeling and can drive cachexia in chronic disease. While essential for host defense, excessive or dysregulated TNF signaling contributes to chronic inflammatory and autoimmune diseases and to septic shock in infection.

Therapeutically, blocking TNF activity with inhibitors has transformed the treatment of several diseases, including rheumatoid arthritis, inflammatory bowel disease, psoriasis, psoriatic arthritis, ankylosing spondylitis, and uveitis. Approved TNF inhibitors include monoclonal antibodies such as infliximab, adalimumab, certolizumab, and golimumab, and the soluble receptor etanercept. Biosimilars are increasingly available.

Risks include infection (notably reactivation of latent tuberculosis), demyelinating events, and rare malignancies; appropriate screening, vaccination, and monitoring are recommended. TNF inhibitors require caution in patients with active infections or heart failure of class III/IV.

TNF was identified in the 1970s and anti-TNF therapies were introduced in the late 1990s.