| IL2 |
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| Available structures |
| PDB |
Ortholog search: PDBe RCSB |
| List of PDB id codes |
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1IRL, 1M47, 1M48, 1M49, 1M4A, 1M4B, 1M4C, 1NBP, 1PW6, 1PY2, 1QVN, 1Z92, 2B5I, 2ERJ, 3QAZ, 3QB1, 3INK, 4NEJ, 4NEM
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| Identifiers |
| Aliases |
IL2, IL-2, TCGF, lymphokine, interleukin 2 |
| External IDs |
OMIM: 147680 MGI: 96548 HomoloGene: 488 GeneCards: IL2 |
| Gene location (Human) |
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| Chr. |
Chromosome 4 (human)[1] |
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| Band |
4q27 |
Start |
122,451,470 bp[1] |
| End |
122,456,725 bp[1] |
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| Gene location (Mouse) |
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| Chr. |
Chromosome 3 (mouse)[2] |
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| Band |
3 B|3 18.3 cM |
Start |
37,120,523 bp[2] |
| End |
37,125,959 bp[2] |
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| RNA expression pattern |
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| More reference expression data |
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| Gene ontology |
| Molecular function |
• cytokine activity
• interleukin-2 receptor binding
• glycosphingolipid binding
• kinase activator activity
• growth factor activity
• kappa-type opioid receptor binding
• carbohydrate binding
• Ras guanyl-nucleotide exchange factor activity
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| Cellular component |
• extracellular region
• cell
• intracellular
• extracellular space
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| Biological process |
• positive regulation of T cell differentiation
• negative regulation of protein phosphorylation
• G-protein coupled receptor signaling pathway
• positive regulation of protein phosphorylation
• positive regulation of inflammatory response
• adaptive immune response
• negative regulation of heart contraction
• immune system process
• positive regulation of cytosolic calcium ion concentration
• positive regulation of regulatory T cell differentiation
• cell-cell signaling
• positive regulation of interferon-gamma production
• natural killer cell activation
• negative regulation of apoptotic process
• positive regulation of dendritic spine development
• negative regulation of lymphocyte proliferation
• MAPK cascade
• regulation of T cell homeostatic proliferation
• T cell differentiation
• positive regulation of cell growth
• protein kinase C-activating G-protein coupled receptor signaling pathway
• cell adhesion
• positive regulation of B cell proliferation
• positive regulation of tissue remodeling
• positive regulation of T cell proliferation
• immune response
• positive regulation of cell proliferation
• extrinsic apoptotic signaling pathway in absence of ligand
• negative regulation of B cell apoptotic process
• positive regulation of isotype switching to IgG isotypes
• positive regulation of interleukin-17 production
• response to ethanol
• positive regulation of immunoglobulin secretion
• negative regulation of inflammatory response
• positive regulation of transcription from RNA polymerase II promoter
• positive regulation of activated T cell proliferation
• positive regulation of GTPase activity
• negative regulation of T-helper 17 cell differentiation
• leukocyte activation involved in immune response
• positive regulation of tyrosine phosphorylation of STAT protein
• regulation of regulatory T cell differentiation
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| Sources:Amigo / QuickGO |
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| Orthologs |
| Species |
Human |
Mouse |
| Entrez |
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| Ensembl |
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| UniProt |
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| RefSeq (mRNA) |
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| RefSeq (protein) |
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| Location (UCSC) |
Chr 4: 122.45 – 122.46 Mb |
Chr 4: 37.12 – 37.13 Mb |
| PubMed search |
[3] |
[4] |
| Wikidata |
| View/Edit Human |
View/Edit Mouse |
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Interleukin-2 (IL-2) is an interleukin, a type of cytokine signaling molecule in the immune system. It is a protein that regulates the activities of white blood cells (leukocytes, often lymphocytes) that are responsible for immunity. IL-2 is part of the body's natural response to microbial infection, and in discriminating between foreign ("non-self") and "self". IL-2 mediates its effects by binding to IL-2 receptors, which are expressed by lymphocytes.
Contents
- 1 Signaling pathway
- 2 Function
- 3 Role in disease
- 4 Medical use
- 4.1 Pharmaceutical analogues
- 4.1.1 Dosage
- 4.1.2 Toxicity
- 4.2 Pharmaceutical derivative
- 5 Clinical research
- 6 History
- 7 References
- 8 External links
Signaling pathway
IL-2 is a member of a cytokine family, each member of which has a four alpha helix bundle; the family also includes IL-4, IL-7, IL-9, IL-15 and IL-21. IL-2 signals through the IL-2 receptor, a complex consisting of three chains, termed alpha, beta and gamma. The gamma chain is shared by all family members.[5]
The IL-2 Receptor (IL-2R) α subunit has low affinity for its ligand but has the ability (when bound to the β and ϒ subunit) to increase the IL-2R affinity 100-fold. Heterodimerization of the β and ϒ subunits of IL-2R is essential for signalling in T cells.[6][7]
Gene expression regulation for IL-2 can be on multiple levels or by different ways. One of the checkpoints is signaling through TCR receptor, antigen receptor of T-lymphocytes after recognizing MHC-peptide complex. Signaling pathway from TCR then goes through phospholipase-C (PLC) dependent pathway. PLC activates 3 major transcription factors and their pathways: NFAT, NFkB and AP-1. After costimulation from CD28 the optimal activation of expression of IL-2 and these pathways is induced.
At the same time Oct-1 is expressed. It helps the activation. Oct1 is expressed in T-lymphocytes adn Oct2 is induced after cell activation.
NFAT has multiple family members, all of them are located in cytoplasm and signaling goes through calcineurin, NFAT is dephosphorylated and therefore translocated to the nucleus.
AP-1 is a dimer and is composed of c-Jun and c-Fos proteins. It cooperates with other transcription factors including NFkB and Oct.
NFkB is translocated to the nucleus after costimulation through CD28. NFkB is a heterodimer and there are two binding sites on the IL-2 promoter.
Function
IL-2 has essential roles in key functions of the immune system, tolerance and immunity, primarily via its direct effects on T cells. In the thymus, where T cells mature, it prevents autoimmune diseases by promoting the differentiation of certain immature T cells into regulatory T cells, which suppress other T cells that are otherwise primed to attack normal healthy cells in the body. IL-2 also promotes the differentiation of T cells into effector T cells and into memory T cells when the initial T cell is also stimulated by an antigen, thus helping the body fight off infections.[5] Its expression and secretion is tightly regulated and functions as part of both transient positive and negative feedback loops in mounting and dampening immune responses. Through its role in the development of T cell immunologic memory, which depends upon the expansion of the number and function of antigen-selected T cell clones, it plays a key role in enduring cell-mediated immunity.[5][8]
Role in disease
While the causes of itchiness are poorly understood, some evidence indicates that IL-2 is involved in itchy psoriasis.[9]
Medical use
Pharmaceutical analogues
Aldesleukin is a form of recombinant interleukin-2. It is manufactured using recombinant DNA technology and is marketed as a protein therapeutic and branded as Proleukin. It has been approved by the Food and Drug Administration (FDA) and in several European countries for the treatment of cancers (malignant melanoma, renal cell cancer) in large intermittent doses and has been extensively used in continuous doses.[10][11][12]
Interking is a recombinant IL-2 with a serine at residue 125, sold by Shenzhen Neptunus.[13]
Dosage
Various dosages of IL-2 across the United States and across the world are used. The efficiency and side effects of different dosages is often a point of disagreement.
United States
Usually, in the U.S., the higher dosage option is used, affected by cancer type, response to treatment and general patient health. Patients are typically treated for five consecutive days, three times a day, for fifteen minutes. The following approximately 10 days help the patient to recover between treatments. IL-2 is delivered intravenously on an inpatient basis to enable proper monitoring of side effects.[14]
A lower dose regimen involves injection of IL-2 under the skin typically on an outpatient basis. It may alternatively be given on an inpatient basis over 1–3 days, similar to and often including the delivery of chemotherapy.[14]
Intralesional IL-2 is commonly used to treat in-transit melanoma metastases and has a high complete response rate.[15]
Toxicity
IL-2 has a narrow therapeutic window, and the level of dosing usually determines the severity of the side effects.[16]
Some common side effects:[14]
- flu-like symptoms (fever, headache, muscle and joint pain, fatigue)
- nausea/vomiting
- dry, itchy skin or rash
- weakness or shortness of breath
- diarrhea
- low blood pressure
- drowsiness or confusion
- loss of appetite
More serious and dangerous side effects sometimes are seen, such as capillary leak syndrome, breathing problems, serious infections, seizures, allergic reactions, heart problems or a variety of other possible complications.[14]
Intralesional IL-2 used to treat in-transit melanoma metastases is generally well-tolerated.[15]
Pharmaceutical derivative
Eisai markets a drug called denileukin diftitox (trade name Ontak), which is a recombinant fusion protein of the human IL-2 ligand and the diphtheria toxin.[17] This drug binds to IL-2 receptors and introduces the diphtheria toxin into cells that express those receptors, killing the cells. In some leukemias and lymphomas, malignant cells express the IL-2 receptor, so denileukin diftitox can kill them. In 1999 Ontak was approved by the U.S. Food and Drug Administration (FDA) for treatment of Cutaneous T-cell Lymphoma (CTCL).[18]
Clinical research
IL-2 has been in clinical trials for the treatment of chronic viral infections and as a booster (adjuvant) for vaccines. The use of large doses of IL-2 given every 6–8 weeks in HIV therapy, similar to its use in cancer therapy, was found to be ineffective in preventing progression to an AIDS diagnosis in two large clinical trials published in 2009.[19]. More recently low dose IL-2 has shown early successful in modulating the immune system in disease like type 1 diabetes and vasculitis [20]. There are also promising studies looking to use low dose IL-2 in ischaemic heart disease [21]. More recently low dose IL-2 has shown early successful in modulating the immune system in disease like type 1 diabetes and vasculitis [22]. There are also promising studies looking to use low dose IL-2 in ischaemic heart disease [23].
History
According to an immunology textbook: "IL-2 is particularly important historically, as it is the first type I cytokine that was cloned, the first type I cytokine for which a receptor component was cloned, and was the first short-chain type I cytokine whose receptor structure was solved. Many general principles have been derived from studies of this cytokine including its being the first cytokine demonstrated to act in a growth factor–like fashion through specific high-affinity receptors, analogous to the growth factors being studied by endocrinologists and biochemists".[24]:712
In the mid-1960s, studies reported "activities" in leukocyte-conditioned media that promoted lymphocyte proliferation.[25]:16 In the mid-1970s, it was discovered that T-cells could be selectively proliferated when normal human bone marrow cells were cultured in conditioned medium obtained from phytohemagglutinin-stimulated normal human lymphocytes.[24]:712 The key factor was isolated from cultured mouse cells in 1979 and from cultured human cells in 1980.[26] The gene for human IL-2 was cloned in 1982 after an intense competition.[27]:76
Commercial activity to bring an IL-2 drug to market was intense in the 1980s and '90s. By 1983, Cetus Corporation had created a proprietary recombinant version of IL-2 (Aldesleukin, later branded as Proleukin), with the alanine removed from its N-terminal and residue 125 replaced with serine.[27]:76–77[28]:201[29] Amgen later entered the field with its own proprietary, mutated, recombinant protein and Cetus and Amgen were soon competing scientifically and in the courts; Cetus won the legal battles and forced Amgen out of the field.[27]:151 By 1990 Cetus had gotten aldesleukin approved in nine European countries but in that year, the U.S. Food and Drug Administration (FDA) refused to approve Cetus' application to market IL-2.[12] The failure led to the collapse of Cetus, and in 1991 the company was sold to Chiron Corporation.[30][31] Chiron continued the development of IL-2, which was finally approved by the FDA as Proleukin for metastatic renal carcinoma in 1992.[32]
By 1993 aldesleukin was the only approved version of IL-2, but Roche was also developing a proprietary, modified, recombinant IL-2 called teceleukin, with a methionine added at is N-terminal, and Glaxo was developing a version called bioleukin, with a methionine added at is N-terminal and residue 125 replaced with alanine. Dozens of clinical trials had been conducted of recombinant or purified IL-2, alone, in combination with other drugs, or using cell therapies, in which cells were taken from patients, activated with IL-2, then reinfused.[29][33] Novartis acquired Chiron in 2006[34] and sold the aldesleukin business to Prometheus Laboratories in 2010.[15]
[35]
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000109471 - Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000027720 - Ensembl, May 2017
- ^ "Human PubMed Reference:".
- ^ "Mouse PubMed Reference:".
- ^ a b c Liao W, Lin JX, Leonard WJ (October 2011). "IL-2 family cytokines: new insights into the complex roles of IL-2 as a broad regulator of T helper cell differentiation". Current Opinion in Immunology. 23 (5): 598–604. PMC 3405730 . PMID 21889323. doi:10.1016/j.coi.2011.08.003.
- ^ Gaffen SL, Liu KD (November 2004). "Overview of interleukin-2 function, production and clinical applications". Cytokine. 28 (3): 109–23. PMID 15473953. doi:10.1016/j.cyto.2004.06.010.
- ^ Gaffen SL, Liu KD (November 2004). "Overview of interleukin-2 function, production and clinical applications". Cytokine. 28 (3): 109–23. PMID 15473953. doi:10.1016/j.cyto.2004.06.010.
- ^ Malek TR, Castro I (August 2010). "Interleukin-2 receptor signaling: at the interface between tolerance and immunity". Immunity. 33 (2): 153–65. PMC 2946796 . PMID 20732639. doi:10.1016/j.immuni.2010.08.004.
- ^ Reich A, Szepietowski JC (2007). "Mediators of pruritus in psoriasis". Mediators of Inflammation. 2007: 64727. PMC 2221678 . PMID 18288273. doi:10.1155/2007/64727.
- ^ Noble S, Goa KL (May 1997). "Aldesleukin (recombinant interleukin-2)". BioDrugs. 7 (5): 394–422. PMID 18031103. doi:10.2165/00063030-199707050-00007.
- ^ Bhatia S, Tykodi SS, Thompson JA (May 2009). "Treatment of metastatic melanoma: an overview". Oncology. 23 (6): 488–96. PMC 2737459 . PMID 19544689.
- ^ a b Pollack A (July 31, 1990). "Cetus Drug Is Blocked By F.D.A.". New York Times. This source mentions approval in 9 European countries.
- ^ Bloombert BusinessWeek. Last updated March 3, 2014 Shenzhen Neptunus Interlng-H
- ^ a b c d American Cancer Society. Interleukin-2 (Aldesleukin). Date accessed: 07 Nov 10.
- ^ a b c Shi VY, Tran K, Patel F, Leventhal J, Konia T, Fung MA, Wilken R, Garcia MS, Fitzmaurice SD, Joo J, Monjazeb AM, Burrall BA, King B, Martinez S, Christensen SD, Maverakis E (October 2015). "100% Complete response rate in patients with cutaneous metastatic melanoma treated with intralesional interleukin (IL)-2, imiquimod, and topical retinoid combination therapy: results of a case series". Journal of the American Academy of Dermatology. 73 (4): 645–54. PMID 26259990. doi:10.1016/j.jaad.2015.06.060.
- ^ Shaker MA, Younes HM (July 2009). "Interleukin-2: evaluation of routes of administration and current delivery systems in cancer therapy". Journal of Pharmaceutical Sciences. 98 (7): 2268–98. PMID 19009549. doi:10.1002/jps.21596.
- ^ Figgitt, DP (2000). "Denileukin diftitox.". Am J Clin Dermatol.
- ^ FDA Page Last Updated: May 11, 2009 Changes in the Ontak (denileukin diftitiox) Package Insert to Include a Description of Ophthalmologic Adverse Events
- ^ "IL-2 Immunotherapy Fails to Benefit HIV-Infected Individuals Already Taking Antiretrovirals". News Release. National Institutes of Health (NIH). February 10, 2009.
- ^ "Low-dose interleukin 2 in patients with type 1 diabetes: a phase 1/2 randomised, double-blind, placebo-controlled trial". Lancet.
- ^ "LILACS Trial".
- ^ "Low-dose interleukin 2 in patients with type 1 diabetes: a phase 1/2 randomised, double-blind, placebo-controlled trial". Lancet.
- ^ "LILACS Trial".
- ^ a b Paul WE (2008). Fundamental immunology (6th ed.). Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins. ISBN 978-0-7817-6519-0.
- ^ Chavez AR, Buchser W, Basse PH, Liang X, Appleman LJ, Maranchie JK, Zeh H, de Vera ME, Lotze MT (December 2009). "Pharmacologic administration of interleukin-2". Annals of the New York Academy of Sciences. 1182: 14–27. PMID 20074271. doi:10.1111/j.1749-6632.2009.05160.x.
- ^ Welte K, Wang CY, Mertelsmann R, Venuta S, Feldman SP, Moore MA (August 1982). "Purification of human interleukin 2 to apparent homogeneity and its molecular heterogeneity". The Journal of Experimental Medicine. 156 (2): 454–64. PMC 2186775 . PMID 6980256. doi:10.1084/jem.156.2.454.
- ^ a b c Rabinow P (1997). Making PCR: A story of biotechnology (Paperback ed.). Chicago, IL, USA: University of Chicago Press. ISBN 978-0226701479.
- ^ Hugo Almeida. Drugs obtained by biotechnology processing Brazilian Journal of Pharmaceutical Sciences apr/jun 2011 47(2):199-207
- ^ a b Whittington R, Faulds D (September 1993). "Interleukin-2. A review of its pharmacological properties and therapeutic use in patients with cancer". Drugs. 46 (3): 446–514. PMID 7693434. doi:10.2165/00003495-199346030-00009.
- ^ "2 Biotech Pioneers To Merge". New York Times. July 23, 1991.
- ^ Lehrman S (January 20, 1992). "Cetus: A Collision Course With Failure". The Scientist Magazine.
- ^ Dutcher JP (November 2002). "Current status of interleukin-2 therapy for metastatic renal cell carcinoma and metastatic melanoma". Oncology. 16 (11 Suppl 13): 4–10. PMID 12469934.
- ^ "D02749 (Teceleukin)". KEGG drug.
- ^ "Chiron shareholders approve Novartis deal". SWI swissinfo.ch. Apr 19, 2006.
- ^ "Novartis sells rights to Proleukin in the USA to Prometheus; gets license for vaccine from IIG; and pleads guilty over Trileptal". Pharmaletter. January 27, 2010.
External links
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Wikimedia Commons has media related to Interleukin-2. |
- Proleukin website
- IL-2 Signaling Pathway
- Rosenberg SA (June 2014). "IL-2: the first effective immunotherapy for human cancer". Journal of Immunology. 192 (12): 5451–8. PMID 24907378. doi:10.4049/jimmunol.1490019.
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PDB gallery
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1irl: THE SOLUTION STRUCTURE OF THE F42A MUTANT OF HUMAN INTERLEUKIN 2
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1m47: Crystal Structure of Human Interleukin-2
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1m48: Crystal Structure of Human IL-2 Complexed with (R)-N-[2-[1-(Aminoiminomethyl)-3-piperidinyl]-1-oxoethyl]-4-(phenylethynyl)-L-phenylalanine methyl ester
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1m49: Crystal Structure of Human Interleukin-2 Complexed with SP-1985
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1m4a: Crystal Structure of Human Interleukin-2 Y31C Covalently Modified at C31 with (1H-Indol-3-yl)-(2-mercapto-ethoxyimino)-acetic acid
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1m4b: Crystal Structure of Human Interleukin-2 K43C Covalently Modified at C43 with 2-[2-(2-Cyclohexyl-2-guanidino-acetylamino)-acetylamino]-N-(3-mercapto-propyl)-propionamide
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1m4c: Crystal Structure of Human Interleukin-2
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1nbp: Crystal Structure Of Human Interleukin-2 Y31C Covalently Modified At C31 With 3-Mercapto-1-(1,3,4,9-tetrahydro-B-carbolin-2-yl)-propan-1-one
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1pw6: Low Micromolar Small Molecule Inhibitor of IL-2
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1py2: Structure of a 60 nM Small Molecule Bound to a Hot Spot on IL-2
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1qvn: Structure of SP4160 Bound to IL-2 V69A
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1z92: structure of interleukin-2 with its alpha receptor
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2b5i: cytokine receptor complex
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2erj: Crystal structure of the heterotrimeric interleukin-2 receptor in complex with interleukin-2
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3ink: UNRAVELING THE STRUCTURE OF INTERLEUKIN-2: REPLY
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Cell signaling: cytokines
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| By family |
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By function/
cell |
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Interleukin receptor modulators
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| IL-1 |
- Agonists: Interleukin 1 (α, β)
- Mobenakin
- Pifonakin
- Antagonists: AF-12198
- Anakinra
- IL-1RA
- Isunakinra
- Antibodies: Canakinumab
- Gevokizumab
- Lutikizumab
- Decoy receptors: Rilonacept (IL-1 Trap)
|
| IL-2 |
- Agonists: Adargileukin alfa
- Aldesleukin
- Celmoleukin
- Denileukin diftitox
- Interleukin 2
- Pegaldesleukin
- Teceleukin
- Tucotuzumab celmoleukin
- Antibodies: Basiliximab
- Daclizumab (dacliximab)
- Inolimomab
|
| IL-3 |
- Agonists: Daniplestim
- Interleukin 3
- Leridistim
- Milodistim
- Muplestim
- Promegapoietin
|
| IL-4 |
- Agonists: Binetrakin
- Interleukin 4
- Interleukin 13
- Antibodies: Dupilumab
- Pascolizumab
|
| IL-5 |
- Antibodies: Benralizumab
- Mepolizumab
- Reslizumab
- Antisense oligonucleotides: TPI ASM8
|
| IL-6 |
- Agonists: Atexakin alfa
- Interleukin 6
- Antibodies: ARGX-109
- Clazakizumab
- Elsilimomab
- mAb 1339
- Olokizumab
- Sarilumab
- Siltuximab
- Sirukumab
- Tocilizumab
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| IL-7 |
|
| IL-8 |
- See CXCR1 (IL-8Rα) and CXCR2 (IL-8Rβ) here instead.
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| IL-9 |
|
| IL-10 |
- Agonists: Ilodecakin
- Interleukin 10 (CSIF)
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| IL-11 |
- Agonists: Interleukin 11 (AGIF)
- Oprelvekin
|
| IL-12 |
- Agonists: Edodekin alfa
- Interleukin 12
- Antibodies: Briakinumab
- Ustekinumab
|
| IL-13 |
- Agonists: Binetrakin
- Cintredekin besudotox
- Interleukin 4
- Interleukin 13
- Antibodies: Anrukinzumab
- Lebrikizumab
- Tralokinumab
|
| IL-15 |
- Agonists: ALT-803
- Interleukin 15
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| IL-17 |
- Agonists: Interleukin 17 (A, B, C, D, E (interleukin 25), F)
- Antibodies: Brodalumab
- Ixekizumab
- Perakizumab
- Remtolumab
- Secukinumab
- Vunakizumab
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| IL-18 |
- Agonists: Iboctadekin
- Interleukin 18
- Interleukin 37
- Tadekinig
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| IL-20 |
- Agonists: Interleukin 19
- Interleukin 20
- Interleukin 24
- Antibodies: Fletikumab (against IL-20)
|
| IL-21 |
- Agonists: Denenicokin
- Interleukin 21
- Antibodies: NNC0114-0005
- NNC0114-0006
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| IL-22 |
- Antibodies: Fezakinumab (against IL-22)
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| IL-23 |
- Agonists: Interleukin 23 (SGRF)
- Antibodies: Brazikumab
- Briakinumab
- Guselkumab
- Tildrakizumab
- Ustekinumab
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| IL-27 |
- Agonists: Interleukin 27 (interleukin 30)
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| IL-28 |
- Agonists: Interferon λ4 (IFN-λ4)
- Interleukin 28 (A (IFN-λ2), B (IFN-λ3))
- Interleukin-29 (IFN-λ1)
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| IL-31 |
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| IL1RL1 |
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| IL1RL2 |
- Agonists: Interleukin 36 (α, β, γ)
- Interleukin 38
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| Others |
| JAK |
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| Others |
- Interleukin 14 (taxilin alpha, HMW-BCGF)
- Interleukin 16 (signals through CD4)
- Interleukin 24 (signals through IL-22Rα1/IL-20Rβ heterodimer)
- Interleukin 26 (signals through IL-20Rα/IL-10Rβ heterodimer)
- Interleukin 32
- Interleukin 34 (signals through M-CSFR/CSF1R)
- Interleukin 35
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- See also
- Receptor/signaling modulators
- Signaling peptide/protein receptor modulators
- Cytokine receptor modulators
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