Lymphotoxin

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.[1]

lymphotoxin alpha (TNF superfamily, member 1)
Identifiers
SymbolLTA
Alt. symbolsTNFB
NCBI gene4049
HGNC6709
OMIM153440
RefSeqNM_000595
UniProtP01374
Other data
LocusChr. 6 p21.3

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.[2][3] 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.[4][5]

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.[4] 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.[4]

Lymphotoxin is produced by lymphocytes upon activation and is involved with various aspects of the immune response, including inflammation and activation signaling.[5] 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.[2][3][5] LT-αβ, which is produced by activated TH1, CD8+ T cells, and natural killer (NK) cells, is known to have a major role in the normal development of Peyer's patches.[6][7] 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.[8]

Receptor binding and signaling activation

In general, lymphotoxin ligands are expressed by immune cells, while their receptors are found on stromal and epithelial cells.[4]

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.[3][5] 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.[2][5] There is also evidence that LTα3 signaling through TNFRI and TNFRII contributes to the regulation of IgA antibody in the gut.[8]

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.[5] 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.[9][10] 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.[2] 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.[3]

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.[11] Studies using mice with an LT-α knockout found increased tumor growth in the absence of LT-αβ.[12]

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.[4][11][13] Mutations in the regulatory factors involved in lymphotoxin signaling may increase the risk of cancer development.[13] 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.[11][13] 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.[13]

See also

References
  1. Nedwin GE, Naylor SL, Sakaguchi AY, Smith D, Jarrett-Nedwin J, Pennica D, et al. (September 1985). "Human lymphotoxin and tumor necrosis factor genes: structure, homology and chromosomal localization". Nucleic Acids Research. 13 (17): 6361–73. doi:10.1093/nar/13.17.6361. PMC 321958. PMID 2995927.
  2. Schlüter D, Deckert M (August 2000). "The divergent role of tumor necrosis factor receptors in infectious diseases". Microbes and Infection. 2 (10): 1285–92. doi:10.1016/S1286-4579(00)01282-X. PMID 11008118.
  3. Benedict CA, Ware CF (October 2001). "Virus targeting of the tumor necrosis factor superfamily". Virology. 289 (1): 1–5. doi:10.1006/viro.2001.1109. PMID 11601911.
  4. Weinstein AM, Storkus WJ (2015). "Therapeutic Lymphoid Organogenesis in the Tumor Microenvironment". Advances in Cancer Research. Elsevier. 128: 197–233. doi:10.1016/bs.acr.2015.04.003. ISBN 978-0-12-802316-7. PMC 4853818. PMID 26216634.
  5. Ruddle NH (April 2014). "Lymphotoxin and TNF: how it all began-a tribute to the travelers". Cytokine & Growth Factor Reviews. 25 (2): 83–9. doi:10.1016/j.cytogfr.2014.02.001. PMC 4027955. PMID 24636534.
  6. Ngo VN, Korner H, Gunn MD, Schmidt KN, Riminton DS, Cooper MD, et al. (January 1999). "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". The Journal of Experimental Medicine. 189 (2): 403–12. doi:10.1084/jem.189.2.403. PMC 2192983. PMID 9892622.
  7. Fundamental immunology. Paul, William E. (6th ed.). Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins. 2008. ISBN 978-0-7817-6519-0. OCLC 195684254.CS1 maint: others (link)
  8. Gubernatorova EO, Tumanov AV (November 2016). "Tumor Necrosis Factor and Lymphotoxin in Regulation of Intestinal Inflammation". Biochemistry. Biokhimiia. 81 (11): 1309–1325. doi:10.1134/S0006297916110092. PMID 27914457. S2CID 15764230.
  9. Müller JR, Siebenlist U (April 2003). "Lymphotoxin beta receptor induces sequential activation of distinct NF-kappa B factors via separate signaling pathways". The Journal of Biological Chemistry. 278 (14): 12006–12. doi:10.1074/jbc.M210768200. PMID 12556537.
  10. Yilmaz ZB, Weih DS, Sivakumar V, Weih F (January 2003). "RelB is required for Peyer's patch development: differential regulation of p52-RelB by lymphotoxin and TNF". The EMBO Journal. 22 (1): 121–30. doi:10.1093/emboj/cdg004. PMC 140043. PMID 12505990.
  11. Bauer J, Namineni S, Reisinger F, Zöller J, Yuan D, Heikenwälder M (2012). "Lymphotoxin, NF-ĸB, and cancer: the dark side of cytokines". Digestive Diseases. 30 (5): 453–68. doi:10.1159/000341690. PMID 23108301. S2CID 13165828.
  12. Korneev KV, Atretkhany KN, Drutskaya MS, Grivennikov SI, Kuprash DV, Nedospasov SA (January 2017). "TLR-signaling and proinflammatory cytokines as drivers of tumorigenesis". Cytokine. 89: 127–135. doi:10.1016/j.cyto.2016.01.021. PMID 26854213.
  13. Fernandes MT, Dejardin E, dos Santos NR (April 2016). "Context-dependent roles for lymphotoxin-β receptor signaling in cancer development". Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 1865 (2): 204–19. doi:10.1016/j.bbcan.2016.02.005. hdl:10400.1/9527. PMID 26923876.

Further reading
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