{{Short description|InterPro Family}} {{infobox protein | Name = lymphotoxin alpha (TNF superfamily, member 1) | caption = | image = | width = | HGNCid = 6709 | Symbol = LTA | AltSymbols = TNFB | EntrezGene = 4049 | OMIM = 153440 | RefSeq = NM_000595 | UniProt = P01374 | PDB = | ECnumber = | Chromosome = 6 | Arm = p | Band = 21.3 | LocusSupplementaryData = }} thumb | right | Structure of the LTA protein. Based on PyMOL rendering of PDB 1tnr. '''Lymphotoxin''' is a member of the tumor necrosis factor (TNF) superfamily of cytokines, whose members are responsible for regulating the growth and function of lymphocytes and are expressed by a wide variety of cells in the body.<ref>{{cite journal | vauthors = Nedwin GE, Naylor SL, Sakaguchi AY, Smith D, Jarrett-Nedwin J, Pennica D, Goeddel DV, Gray PW | display-authors = 6 | title = Human lymphotoxin and tumor necrosis factor genes: structure, homology and chromosomal localization | journal = Nucleic Acids Research | volume = 13 | issue = 17 | pages = 6361–73 | date = September 1985 | pmid = 2995927 | pmc = 321958 | doi = 10.1093/nar/13.17.6361 }}</ref>
Lymphotoxin plays a critical role in developing and preserving the framework of lymphoid organs and of gastrointestinal immune responses, as well as in the activation signaling of both the innate and adaptive immune responses.<ref name="Schlüter_2000">{{cite journal | vauthors = Schlüter D, Deckert M | title = The divergent role of tumor necrosis factor receptors in infectious diseases | journal = Microbes and Infection | volume = 2 | issue = 10 | pages = 1285–92 | date = August 2000 | pmid = 11008118 | doi = 10.1016/S1286-4579(00)01282-X }}</ref><ref name="Benedict_2001">{{cite journal | vauthors = Benedict CA, Ware CF | title = Virus targeting of the tumor necrosis factor superfamily | journal = Virology | volume = 289 | issue = 1 | pages = 1–5 | date = October 2001 | pmid = 11601911 | doi = 10.1006/viro.2001.1109 | doi-access = free }}</ref> Lymphotoxin alpha (LT-α, previously known as TNF-beta) and lymphotoxin beta (LT-β), the two forms of lymphotoxin, each have distinctive structural characteristics and perform specific functions.<ref name="Weinstein_2015">{{cite journal | vauthors = Weinstein AM, Storkus WJ | title = Therapeutic Lymphoid Organogenesis in the Tumor Microenvironment | journal = Advances in Cancer Research | volume = 128 | pages = 197–233 | date = 2015 | pmid = 26216634 | pmc = 4853818 | doi = 10.1016/bs.acr.2015.04.003 | publisher = Elsevier | isbn = 978-0-12-802316-7 }}</ref><ref name="Ruddle_2014">{{cite journal | vauthors = Ruddle NH | title = Lymphotoxin and TNF: how it all began-a tribute to the travelers | journal = Cytokine & Growth Factor Reviews | volume = 25 | issue = 2 | pages = 83–9 | date = April 2014 | pmid = 24636534 | pmc = 4027955 | doi = 10.1016/j.cytogfr.2014.02.001 }}</ref>
== Structure and function== Each LT-α/LT-β subunit is a trimer and assembles into homotrimers or heterotrimers. LT-α binds with LT-β to form membrane-bound heterotrimers LT-α1-β2 and LT-α2-β1, which are commonly referred to as lymphotoxin beta.<ref name="Weinstein_2015" /> LT-α1-β2 is the most prevalent form of lymphotoxin beta. LT-α also forms a homotrimer, LT-α3, which is secreted by activated lymphocytes as a soluble protein.<ref name="Weinstein_2015" />
Lymphotoxin is produced by lymphocytes upon activation and is involved with various aspects of the immune response, including inflammation and activation signaling.<ref name="Ruddle_2014" /> Upon binding to the LTβ receptor, LT-αβ transmits signals leading to proliferation, homeostasis and activation of tissue cells in secondary lymphoid organs through induced expression of chemokines, major histocompatibility complex, and adhesion molecules.<ref name="Schlüter_2000" /><ref name="Benedict_2001" /><ref name="Ruddle_2014" /> LT-αβ, which is produced by activated Type 1 T helper cells (T<sub>h</sub>1), CD8+ T cells, and natural killer (NK) cells, is known to have a major role in the normal development of Peyer's patches.<ref>{{cite journal | vauthors = Ngo VN, Korner H, Gunn MD, Schmidt KN, Riminton DS, Cooper MD, Browning JL, Sedgwick JD, Cyster JG | display-authors = 6 | title = Lymphotoxin alpha/beta and tumor necrosis factor are required for stromal cell expression of homing chemokines in B and T cell areas of the spleen | journal = The Journal of Experimental Medicine | volume = 189 | issue = 2 | pages = 403–12 | date = January 1999 | pmid = 9892622 | pmc = 2192983 | doi = 10.1084/jem.189.2.403 }}</ref><ref>{{Cite book|title=Fundamental immunology|date=2008|publisher=Wolters Kluwer/Lippincott Williams & Wilkins|others=Paul, William E.|isbn=978-0-7817-6519-0|edition=6th|location=Philadelphia|oclc=195684254}}</ref> Studies have found that mice with an inactivated LT-α gene (LTA) lack developed Peyer's patches and lymph nodes. In addition, LT-αβ is necessary for the proper formation of the gastrointestinal immune system.<ref name="Gubernatorova_2016">{{cite journal | vauthors = Gubernatorova EO, Tumanov AV | title = Tumor Necrosis Factor and Lymphotoxin in Regulation of Intestinal Inflammation | journal = Biochemistry. Biokhimiia | volume = 81 | issue = 11 | pages = 1309–1325 | date = November 2016 | pmid = 27914457 | doi = 10.1134/S0006297916110092 | s2cid = 15764230 }}</ref>
=== Receptor binding and signaling activation === In general, lymphotoxin ligands are expressed by immune cells, while their receptors are found on stromal and epithelial cells.<ref name="Weinstein_2015" />
The lymphotoxin homotrimer and heterotrimers are specific to different receptors. The LT-αβ complexes are the primary ligands for the lymphotoxin beta receptor (LTβR), which is expressed on tissue cells in multiple lymphoid organs, as well as on monocytes and dendritic cells.<ref name="Benedict_2001" /><ref name="Ruddle_2014" /> The soluble LT-α homotrimer binds to TNF receptors 1 and 2 (TNFR-1 and TNFR-2), and the herpesvirus entry mediator, expressed on T cells, dendritic cells, macrophages, and epithelial cells.<ref name="Schlüter_2000" /><ref name="Ruddle_2014" /> There is also evidence that LTα3 signaling through TNFRI and TNFRII contributes to the regulation of IgA antibody in the gut.<ref name="Gubernatorova_2016" />
Lymphotoxin administers a variety of activation signals in the innate immune response. LT-α is necessary for the expression of LT-α1-β2 on the cell surface as LT-α aids in the movement of LT-β to the cell surface to form LT-α1-β2.<ref name="Ruddle_2014" /> In the LT-α mediated signaling pathway, LT-α binds with LT-β to form the membrane-bound LT-α1-β2 complex. Binding of LT-α1-β2 to the LT-β receptor on the target cell can activate various signaling pathways in the effector cell such as the activation of the NF-κB pathway, a major signaling pathway that results in the release of additional pro-inflammatory cytokines essential for the innate response.<ref>{{cite journal | vauthors = Müller JR, Siebenlist U | title = Lymphotoxin beta receptor induces sequential activation of distinct NF-kappa B factors via separate signaling pathways | journal = The Journal of Biological Chemistry | volume = 278 | issue = 14 | pages = 12006–12 | date = April 2003 | pmid = 12556537 | doi = 10.1074/jbc.M210768200 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Yilmaz ZB, Weih DS, Sivakumar V, Weih F | title = RelB is required for Peyer's patch development: differential regulation of p52-RelB by lymphotoxin and TNF | journal = The EMBO Journal | volume = 22 | issue = 1 | pages = 121–30 | date = January 2003 | pmid = 12505990 | pmc = 140043 | doi = 10.1093/emboj/cdg004 }}</ref> The binding of lymphotoxin to LT-β receptors is essential for the recruitment of B cells and cytotoxic (CD8+) T cells to specific lymphoid sites to allow the clearing of antigen.<ref name="Schlüter_2000" /> Signaling of the LT-β receptors can also induce the differentiation of NK (natural killer) and NK-T cells, which are key players in the innate immune defense and in antiviral responses.<ref name="Benedict_2001" />
== Carcinogenic interactions== Lymphotoxin has cytotoxic properties that can aid in the destruction of tumor cells and promote the death of cancerous cells. The activation of LT-β receptors causes an up-regulation of adhesion molecules and directs B and T cells to specific sites to destroy tumor cells.<ref name="Bauer_2012">{{cite journal | vauthors = Bauer J, Namineni S, Reisinger F, Zöller J, Yuan D, Heikenwälder M | title = Lymphotoxin, NF-ĸB, and cancer: the dark side of cytokines | journal = Digestive Diseases | volume = 30 | issue = 5 | pages = 453–68 | date = 2012 | pmid = 23108301 | doi = 10.1159/000341690 | s2cid = 13165828 | url = https://www.karger.com/Article/FullText/341690 | url-access = subscription }}</ref> Studies using mice with an LT-α knockout found increased tumor growth in the absence of LT-αβ.<ref>{{cite journal | vauthors = Korneev KV, Atretkhany KN, Drutskaya MS, Grivennikov SI, Kuprash DV, Nedospasov SA | title = TLR-signaling and proinflammatory cytokines as drivers of tumorigenesis | journal = Cytokine | volume = 89 | pages = 127–135 | date = January 2017 | pmid = 26854213 | doi = 10.1016/j.cyto.2016.01.021 }}</ref>
However, some studies using cancer models have found that a high expression of lymphotoxin can lead to increased growth of tumors and cancerous cell lines. The signaling of the LT-β receptor may induce the inflammatory properties of specific cancerous cell lines, and that the elimination of LT-β receptors may hinder tumor growth and lower inflammation.<ref name="Weinstein_2015" /><ref name="Bauer_2012" /><ref name="Fernandes_2016">{{cite journal | vauthors = Fernandes MT, Dejardin E, dos Santos NR | title = Context-dependent roles for lymphotoxin-β receptor signaling in cancer development | journal = Biochimica et Biophysica Acta (BBA) - Reviews on Cancer | volume = 1865 | issue = 2 | pages = 204–19 | date = April 2016 | pmid = 26923876 | doi = 10.1016/j.bbcan.2016.02.005 | hdl = 10400.1/9527 | hdl-access = free }}</ref> Mutations in the regulatory factors involved in lymphotoxin signaling may increase the risk of cancer development.<ref name="Fernandes_2016" /> One major instance is the continuous initiation of the NF-κB pathway due to an excessive binding of the LT-α1-β2 complex to LT-β receptors, which can lead to specific cancerous conditions including multiple myeloma and melanoma.<ref name="Bauer_2012" /><ref name="Fernandes_2016" /> As excessive inflammation can result in cell damage and a higher risk of the growth of cancer cells, mutations that affect the regulation of LT-α pro-inflammatory signaling pathways can increase the potential for cancer and tumor cell development.<ref name="Fernandes_2016" />
== See also == * Lymphotoxin beta receptor * Tumor necrosis factor-alpha#Discovery
== References == {{Reflist}}
== Further reading == {{refbegin}} * {{cite journal | vauthors = Schlüter D, Deckert M | title = The divergent role of tumor necrosis factor receptors in infectious diseases | journal = Microbes and Infection | volume = 2 | issue = 10 | pages = 1285–92 | date = August 2000 | pmid = 11008118 | doi = 10.1016/S1286-4579(00)01282-X }} * {{cite journal | vauthors = Zhu M, Fu YX | title = The role of core TNF/LIGHT family members in lymph node homeostasis and remodeling | journal = Immunological Reviews | volume = 244 | issue = 1 | pages = 75–84 | date = November 2011 | pmid = 22017432 | doi = 10.1111/j.1600-065X.2011.01061.x | s2cid = 44057024 }} * {{cite journal | vauthors = Benedict CA, Ware CF | title = Virus targeting of the tumor necrosis factor superfamily | journal = Virology | volume = 289 | issue = 1 | pages = 1–5 | date = October 2001 | pmid = 11601911 | doi = 10.1006/viro.2001.1109 | doi-access = free }} * {{cite journal | vauthors = Ruddle NH | title = Lymphotoxin and TNF: how it all began-a tribute to the travelers | journal = Cytokine & Growth Factor Reviews | volume = 25 | issue = 2 | pages = 83–9 | date = April 2014 | pmid = 24636534 | pmc = 4027955 | doi = 10.1016/j.cytogfr.2014.02.001 }} {{refend}}
== External links == * {{MeshName|Lymphotoxin}}
{{Cytokines}} {{TNF receptor superfamily modulators}}
Category:Cytokines