Lymphotoxin-alpha (LT-α) formerly known as tumor necrosis factor-beta (TNF-β) is an immune signalling protein (a cytokine) that in humans is encoded by the LTA gene. LT-α is a mainly produced by activated lymphocytes, with particularly strong expression by certain T cell and B cell subsets. It exhibits anti-proliferative activity and causes the cellular destruction of tumor cell lines. As a cytotoxic protein, LT-α performs a variety of important roles in immune regulation depending on the form that it is secreted as. Unlike other members of the TNF superfamily, in soluble form LT-α is only found as a homotrimer. At the cell surface it is found only as a heterotrimer with the membrane-anchored protein LTβ. LT-α has a significant impact on the maintenance of the immune system including the development of secondary lymphoid organs. Absence of LT-α leads to the disruption of gastrointestinal development, prevents Peyer's patch development, and results in a disorganized spleen. As a signaling molecule, LT-α is involved in the regulation of cell survival, proliferation, differentiation, and apoptosis. LT-α plays an important role in innate immune regulation and its presence has been shown to prevent tumor growth and destroy cancerous cell lines. In contrast, unregulated expression of LT-α can result in a constantly active signaling pathway, thus leading to uncontrolled cellular growth and creation of tumors. Hence depending on the context, LT-α may function to prevent growth of cancer cells or facilitate the development of tumors. Furthermore, LT-α effects depend on the type of organ it acts upon, type of cancer cells, cellular environment, gender, and time of effect during an immune response.
Gene The human gene encoding for LT-α was cloned in 1985. The gene of LT-α is located on chromosome 6 and is in close proximity of the gene encoding major histocompatibility complex.
Structure LT-α is translated as a 25 kDa glycosylated polypeptide with 171 amino acid residues. Furthermore, human LT-α is 72% identical to mouse LT-α at the protein's primary sequence. LTα expression is highly inducible and when secreted, forms a soluble homotrimeric molecule. LT-α can also form heterotrimers with lymphotoxin-beta, which anchors lymphotoxin-alpha to the cell surface. The interaction between LT-α and LT-β results in the formation of a membrane bound complex (LT-α1-β2).
Function Lymphotoxin alpha, a member of the tumor necrosis factor superfamily, is a cytokine produced by lymphocytes. It occurs as soluble homotrimer (LT-α3) and as membrane-bound heterotrimer (LT-α1-β2) with LT-β. Soluble LT-α3 binds TNFR1 and TNFR2 and can induce apoptosis or growth arrest in sensitive target cells, contribute to anti-tumor and antiviral cytotoxicity, and promote inflammatory cytokine production via NF-κB signaling. Membrane LT-α1-β2 signals through LT-β receptors and is crucial for lymphoid organogenesis, maintenance of secondary lymphoid tissues (lymph nodes, Peyer’s patches), and formation of tertiary lymphoid structures in chronic inflammation. Absence of LT-β on the lymphocyte cell surface will diminish the ability of LT-α to form LT-α1-β2, thus decreasing its effective ability as a cytokine. LT-α mediates a large variety of inflammatory, immunostimulatory, and antiviral responses in target cells. LT-α is also involved in the formation of secondary lymphoid organs during development and plays a role in apoptosis. In LT-α knockout mice, Peyer's patches and lymph nodes will fail to develop, thus illustrating the cytokine's essential role in immunological development. As a cytotoxic protein, LT-α causes the destruction of cancerous cell lines, activates signaling pathways, and effectively kills transformed tumor cells. However, mice with overexpression of LT-α or LT-β showed increased tumor growth and metastasis in several models of cancer. In other studies, mice with gene knockout of LT-α showed enhanced tumor growth, implicating possible protective role of LT-α in cancer. However, these studies utilized mice with complete LT-α deficiency that did not allow to distinguish effects of soluble versus membrane-associated LT.
LT-α mediated signaling pathway As a member of the TNF family, LT-α binds to various receptors and activates the NF-κB pathway, thus promoting immune regulation through the innate immune response. In order for activation via LT-β receptor to occur, LT-α must form a complex with LT-β to form the LT-α1-β2 complex in the plasma membrane of the lymphocyte. Formation of LT-α1-β2 complex enables binding to LT-β receptors on target cells and subsequent activation of signaling pathways. Activation of signaling pathways such as NF-κB ultimately leads to various cellular fates, including cell proliferation and cell death. After LT-β receptor activation, IKK-α, β, and γ are produced, which increases degradation of I-κB, an inhibitor of NF-kB, and produce NF-kB1 (p50) and ReIA (p60). The production of NF-kB1 and ReIA increases rates of gene transcription of cytokines and inflammatory-inducing molecules.
Anti-carcinogenic properties Activation of LT-β receptors is capable of inducing cell death of cancerous cells and suppressing tumor growth. The process of cell death is mediated by the presence of IFN-γ and can involve apoptotic or necrotic pathways. It is seen that LT-β receptors facilitate the upregulation of adhesion molecules and recruit lymphocytes to tumor cells to combat tumor growth. In other words, LT-α interactions with LT-β receptors can increase anti-tumor effects through direct destruction of tumor cells.
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