Tumor necrosis factor-α (TNF-α)

Tumor Necrosis Factor (TNF) is a key inflammatory cytokine primarily produced by activated monocytes and macrophages. It plays a crucial role in the immune response, exhibiting a wide range of biological activities such as tumor cell cytotoxicity, enhancement of phagocytosis, fever induction, and the stimulation of acute phase protein synthesis in hepatocytes. TNF also promotes the differentiation of myeloid leukemia cells into macrophages and influences cell proliferation and differentiation. It is involved in both physiological and pathological processes, including autoimmune diseases and infectious responses. There are two main forms of TNF: TNF-α and TNF-β. TNF-α is mainly secreted by mononuclear-macrophage cells, while TNF-β is produced by activated T lymphocytes. Both have similar pyrogenic properties, with low doses causing unimodal fever and high doses leading to bimodal fever. TNF-α synergizes with interferon to enhance anti-tumor effects and stimulates the production of interleukin-1 (IL-1) both in vitro and in vivo. The discovery of TNF dates back to 1975 when Carswell et al. identified a factor in mice that could kill tumor cells or cause tumor necrosis. In 1985, Shalaby named the macrophage-derived form TNF-α and the T-cell derived form TNF-β. TNF-α is also known as cachectin due to its role in inducing weight loss and muscle wasting. TNF is produced by various cell types, including monocytes, macrophages, T lymphocytes, B cells, neutrophils, and endothelial cells. The production can be stimulated by lipopolysaccharide (LPS), interferon-gamma (IFN-γ), granulocyte-macrophage colony-stimulating factor (GM-CSF), and other factors. However, prostaglandin E2 (PGE) can inhibit TNF production. The molecular structure of TNF-α consists of a precursor with 233 amino acids, which is processed to a mature form of 157 amino acids. It contains two cysteine residues that form intramolecular disulfide bonds. The human TNF-α gene is located on chromosome 6, while the mouse TNF-α gene is on chromosome 17. Both genes share high sequence homology and encode proteins with similar biological functions. TNF exerts its effects through two types of receptors: TNF receptor type I (55 kDa) and type II (75 kDa). These receptors are part of the nerve growth factor receptor (NGFR) superfamily and play different roles in signal transduction. Soluble forms of TNF receptors (sTNFR) can bind TNF and modulate its activity, acting as natural inhibitors. TNF has diverse biological effects, including direct tumor cell killing, enhancing immune responses, promoting inflammation, and regulating coagulation. It also plays a role in viral infections, where it may inhibit viral replication. However, excessive TNF levels are associated with pathologies such as septic shock, autoimmune diseases, and certain cancers. Clinically, TNF has been explored for use in cancer treatment, particularly in combination with other therapies. Despite its potential, systemic administration is limited by toxicity, so localized delivery methods like intralesional injection are preferred. Gene therapy approaches targeting TNF are also under investigation. In summary, TNF is a multifunctional cytokine with critical roles in immunity, inflammation, and disease. Its complex interactions with other molecules and pathways make it a key player in both health and pathology. Continued research into TNF's mechanisms and applications holds promise for developing new therapeutic strategies.

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