Lymphotoxin

Last updated
lymphotoxin alpha (TNF superfamily, member 1)
Identifiers
Symbol LTA
Alt. symbolsTNFB
NCBI gene 4049
HGNC 6709
OMIM 153440
RefSeq NM_000595
UniProt P01374
Other data
Locus Chr. 6 p21.3

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]

Contents

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

Related Research Articles

Cytokine Broad and loose category of small proteins important in cell signaling

Cytokines are a broad and loose category of small proteins important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrine, paracrine and endocrine signaling as immunomodulating agents. Their definite distinction from hormones is still part of ongoing research.

Tumor necrosis factor Protein

Tumor necrosis factor is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homologous TNF domain.

Transforming growth factor beta Cytokine

Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms and many other signaling proteins. TGFB proteins are produced by all white blood cell lineages.

TRAIL

In the field of cell biology, TNF-related apoptosis-inducing ligand (TRAIL), is a protein functioning as a ligand that induces the process of cell death called apoptosis.

TGF beta 1 Protein-coding gene in the species Homo sapiens

Transforming growth factor beta 1 or TGF-β1 is a polypeptide member of the transforming growth factor beta superfamily of cytokines. It is a secreted protein that performs many cellular functions, including the control of cell growth, cell proliferation, cell differentiation, and apoptosis. In humans, TGF-β1 is encoded by the TGFB1 gene.

TNF receptor superfamily Protein superfamily of cytokine receptors

The tumor necrosis factor receptor superfamily (TNFRSF) is a protein superfamily of cytokine receptors characterized by the ability to bind tumor necrosis factors (TNFs) via an extracellular cysteine-rich domain. With the exception of nerve growth factor (NGF), all TNFs are homologous to the archetypal TNF-alpha. In their active form, the majority of TNF receptors form trimeric complexes in the plasma membrane. Accordingly, most TNF receptors contain transmembrane domains (TMDs), although some can be cleaved into soluble forms, and some lack a TMD entirely. In addition, most TNF receptors require specific adaptor protein such as TRADD, TRAF, RIP and FADD for downstream signalling. TNF receptors are primarily involved in apoptosis and inflammation, but they can also take part in other signal transduction pathways, such as proliferation, survival, and differentiation. TNF receptors are expressed in a wide variety of tissues in mammals, especially in leukocytes.

TRAF2 Protein-coding gene in the species Homo sapiens

TNF receptor-associated factor 2 is a protein that in humans is encoded by the TRAF2 gene.

Lymphotoxin beta receptor

Lymphotoxin beta receptor (LTBR), also known as tumor necrosis factor receptor superfamily member 3 (TNFRSF3), is a cell surface receptor for lymphotoxin involved in apoptosis and cytokine release. It is a member of the tumor necrosis factor receptor superfamily.

Lymphotoxin alpha Protein-coding gene in the species Homo sapiens

Lymphotoxin-alpha (LT-α) or tumor necrosis factor-beta (TNF-β) is a protein that in humans is encoded by the LTA gene. Belonging to the hematopoietic cell line, LT-α 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, LT-α is only found as a soluble homotrimer, when found at the cell surface it is found only as a heterotrimer with LTβ.

TRAF3 Protein-coding gene in the species Homo sapiens

TNF receptor-associated factor (TRAF3) is a protein that in humans is encoded by the TRAF3 gene.

Lymphotoxin beta

Lymphotoxin-beta (LT-beta) also known as tumor necrosis factor C (TNF-C) is a protein that in humans is encoded by the LTB gene.

MAP3K14

Mitogen-activated protein kinase kinase kinase 14 also known as NF-kappa-B-inducing kinase (NIK) is an enzyme that in humans is encoded by the MAP3K14 gene.

LIGHT (protein) Secreted protein of the TNF superfamily

LIGHT, also known as tumor necrosis factor superfamily member 14 (TNFSF14), is a secreted protein of the TNF superfamily. It is recognized by herpesvirus entry mediator (HVEM), as well as decoy receptor 3.

TNFRSF18

Tumor necrosis factor receptor superfamily member 18 (TNFRSF18), also known as glucocorticoid-induced TNFR-related protein (GITR) or CD357. GITR is encoded and tnfrsf18 gene at chromosome 4 in mice. GITR is type I transmembrane protein and is described in 4 different isoforms. GITR human orthologue, also called activation-inducible TNFR family receptor (AITR), is encoded by the TNFRSF18 gene at chromosome 1.

Death receptor 6

Death receptor 6 (DR6), also known as tumor necrosis factor receptor superfamily member 21 (TNFRSF21), is a cell surface receptor of the tumor necrosis factor receptor superfamily which activates the JNK and NF-κB pathways. It is mostly expressed in the thymus, spleen and white blood cells. The Gene for DR6 is 78,450 bases long and is found on the 6th chromosome. This is transcribed into a 655 amino acid chain weighing 71.8 kDa. Post transcriptional modifications of this protein include glycosylation on the asparagines at the 82, 141, 252, 257, 278, and 289 amino acid locations.

The following outline is provided as an overview of and topical guide to immunology:

An inflammatory cytokine or proinflammatory cytokine is a type of signaling molecule that is secreted from immune cells like helper T cells (Th) and macrophages, and certain other cell types that promote inflammation. They include interleukin-1 (IL-1), IL-6, IL-12, and IL-18, tumor necrosis factor alpha (TNF-α), interferon gamma (IFNγ), and granulocyte-macrophage colony stimulating factor (GM-CSF) and play an important role in mediating the innate immune response. Inflammatory cytokines are predominantly produced by and involved in the upregulation of inflammatory reactions.

Interleukin-1 family Group of cytokines playing a key role in the regulation of immune and inflammatory responses

The Interleukin-1 family is a group of 11 cytokines that plays a central role in the regulation of immune and inflammatory responses to infections or sterile insults.

Innate lymphoid cells (ILCs) are the most recently discovered family of innate immune cells, derived from common lymphoid progenitors (CLPs). In response to pathogenic tissue damage, ILCs contribute to immunity via the secretion of signalling molecules, and the regulation of both innate and adaptive immune cells. ILCs are primarily tissue resident cells, found in both lymphoid, and non- lymphoid tissues, and rarely in the blood. They are particularly abundant at mucosal surfaces, playing a key role in mucosal immunity and homeostasis. Characteristics allowing their differentiation from other immune cells include the regular lymphoid morphology, absence of rearranged antigen receptors found on T cells and B cells, and phenotypic markers usually present on myeloid or dendritic cells.

Immunology is the study of the immune system during health and disease. Below is a list of immunology-related articles.

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. 1 2 3 4 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. 1 2 3 4 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. 1 2 3 4 5 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. 1 2 3 4 5 6 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.{{cite book}}: CS1 maint: others (link)
  8. 1 2 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. 1 2 3 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. 1 2 3 4 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

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.