Tumor necrosis factor-α (TNF-α)

Tumor Necrosis Factor (TNF) is a cytokine primarily produced by activated monocytes and macrophages. It plays a crucial role in the immune response, exhibiting multiple biological functions such as tumor cell inhibition, enhancement of phagocytosis by neutrophils, resistance to infections, fever induction, and stimulation of acute phase protein synthesis in hepatocytes. TNF also promotes the differentiation of myeloid leukemia cells into macrophages and contributes to the proliferation and differentiation of various cell types. As an important inflammatory mediator, it is involved in the pathogenesis of certain autoimmune diseases. 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 a unimodal fever and high doses resulting in a bimodal fever pattern. TNF has been shown to stimulate the production of interleukin-1 (IL-1) both in vitro and in vivo. It is also capable of inducing the production of IL-6, thereby contributing to the overall inflammatory response. 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 after exposure to bacterial lipopolysaccharides (LPS). In 1985, Shalaby classified this factor as TNF-α, while lymphotoxin was named TNF-β. TNF-α is also known as cachectin due to its involvement in weight loss and muscle wasting. TNF is produced by a variety of cell types, including monocytes, macrophages, T lymphocytes, B cells, neutrophils, and even endothelial cells. The production of TNF-α can be stimulated by factors such as LPS, interferon-gamma (IFN-γ), M-CSF, and GM-CSF, while prostaglandin E (PGE) has an inhibitory effect. Different cell lines, such as U937 and HL-60, can produce higher levels of TNF-α under stimulation with phorbol myristate acetate (PMA). Molecularly, human TNF-α consists of 233 amino acid residues, with a mature form of 157 residues. It is non-glycosylated and contains two cysteines forming intramolecular disulfide bonds. The mouse homologue has a similar structure but includes a glycosylation site that does not affect its biological activity. TNF-α exhibits significant sequence homology between species, suggesting conserved functions across different organisms. TNF receptors (TNFRs) are divided into two types: type I (55 kDa, CD120a) and type II (75 kDa, CD120b). These receptors are part of the nerve growth factor receptor (NGFR) superfamily and are expressed on various cell types. Soluble forms of TNFR, known as sTNFR, can bind to TNF and modulate its activity, playing a regulatory role in the cytokine network. Elevated levels of soluble TNFR have been observed in conditions such as inflammation, sepsis, and certain cancers. Biologically, TNF exerts a wide range of effects. It can directly kill or inhibit tumor cells, enhance neutrophil phagocytosis, exhibit antiviral activity, induce fever, promote the differentiation of myeloid leukemia cells, and stimulate cell proliferation. Its mechanisms include lysosomal disruption, activation of phospholipase A2, and modulation of glucose metabolism. TNF also enhances immune responses by promoting the expression of major histocompatibility complex (MHC) class II antigens and increasing the production of other cytokines like IL-1 and IL-6. In clinical settings, TNF has been explored for use in cancer treatment, particularly in combination with other therapies such as IL-2. However, systemic administration is often associated with significant side effects, making localized delivery methods more favorable. TNF gene therapy has also been investigated for treating certain malignancies. Despite its beneficial roles, TNF is implicated in the pathogenesis of several diseases, including septic shock, viral infections, and autoimmune disorders. Excessive TNF production can lead to severe complications, and anti-TNF therapies are being evaluated for their efficacy in managing these conditions. Overall, TNF is a multifunctional cytokine with critical roles in immunity, inflammation, and disease. Its complex interactions and diverse effects make it an important target for therapeutic interventions.

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