Editing Interleukin 2

{{Short description|Mammalian protein found in humans}}
{{Infobox_gene}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
'''Interleukin-2''' ('''IL-2''') is an [[interleukin]], which is a type of [[cytokine]] signaling molecule forming part of the [[immune system]]. It is a 15.5&ndash;16&nbsp;[[Dalton (unit)|kDa]] [[protein]]<ref name=":0">{{cite journal | vauthors = Arenas-Ramirez N, Woytschak J, Boyman O | title = Interleukin-2: Biology, Design and Application | journal = Trends in Immunology | volume = 36 | issue = 12 | pages = 763–777 | date = December 2015 | pmid = 26572555 | doi = 10.1016/j.it.2015.10.003 | s2cid = 3621867 | url = https://www.zora.uzh.ch/id/eprint/123112/1/1-s2.0-S1471490615002483-main.pdf }}</ref> that regulates the activities of [[white blood cell]]s (leukocytes, often [[lymphocyte]]s) that are responsible for immunity. IL-2 is part of the body's [[immune response|natural response]] to [[microbial]] [[infection]], and in discriminating between foreign ("non-self") and "self". IL-2 mediates its effects by binding to [[IL-2 receptor]]s, which are expressed by lymphocytes. The major sources of IL-2 are activated [[T helper cell|CD4<sup>+</sup> T cells]] and activated [[CD8+ T cells|CD8<sup>+</sup> T cells]].<ref name="Liao_2011" /> Put shortly the function of IL-2 is to stimulate the growth of helper, cytotoxic and regulatory T cells.
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== IL-2 receptor  ==

IL-2 is a member of a specific family of cytokines, each member of which has a [[Helix bundle#Four-helix bundles|four alpha helix bundle]]; this cytokine family also includes [[Interleukin-4|IL-4]], [[Interleukin 7|IL-7]], [[Interleukin 9|IL-9]], [[Interleukin 15|IL-15]] and [[Interleukin 21|IL-21]]. IL-2 signals through a [[IL-2 receptor]], a complex consisting of three chains, termed alpha ([[IL2RA|CD25]]), beta ([[IL2RB|CD122]]) and [[Common gamma chain|gamma]] ([[Common gamma chain|CD132]]). The gamma chain is common to all family members.<ref name="Liao_2011">{{cite journal | vauthors = Liao W, Lin JX, Leonard WJ | title = IL-2 family cytokines: new insights into the complex roles of IL-2 as a broad regulator of T helper cell differentiation | journal = Current Opinion in Immunology | volume = 23 | issue = 5 | pages = 598–604 | date = October 2011 | pmid = 21889323 | pmc = 3405730 | doi = 10.1016/j.coi.2011.08.003 }}</ref>

The IL-2 receptor (IL-2R) α subunit binds IL-2 with low affinity (K<sub>d</sub>~ 10<sup>−8</sup> M). Interaction of IL-2 and CD25 alone does not lead to signal transduction due to its short intracellular chain but has the ability (when bound to the β and γ subunit) to increase the IL-2R affinity 100-fold.<ref name=":1">{{cite journal | vauthors = Wang X, Rickert M, Garcia KC | title = Structure of the quaternary complex of interleukin-2 with its alpha, beta, and gammac receptors | journal = Science | volume = 310 | issue = 5751 | pages = 1159–63 | date = November 2005 | pmid = 16293754 | doi = 10.1126/science.1117893 | bibcode = 2005Sci...310.1159W | s2cid = 85394260 }}</ref><ref name=":0" /> Heterodimerization of the β and γ subunits of IL-2R is essential for signalling in [[T cell]]s.<ref name="Gaffen_2004">{{cite journal | vauthors = Gaffen SL, Liu KD | title = Overview of interleukin-2 function, production and clinical applications | journal = Cytokine | volume = 28 | issue = 3 | pages = 109–23 | date = November 2004 | pmid = 15473953 | doi = 10.1016/j.cyto.2004.06.010 }}</ref> IL-2 can signalize either via intermediate-affinity dimeric CD122/CD132 IL-2R (K<sub>d</sub>~ 10<sup>−9</sup> M) or high-affinity trimeric CD25/CD122/CD132 IL-2R (K<sub>d</sub>~ 10<sup>−11</sup> M).<ref name=":1" /> Dimeric IL-2R is expressed by memory CD8<sup>+</sup> T cells and [[NK cells]], whereas [[regulatory T cell]]s and activated T cells express high levels of trimeric IL-2R.<ref name=":0" />

== IL-2 signaling pathways and regulation ==
Instructions to express proteins in response to an IL-2 signal (called IL-2 transduction) can take place via 3 different [[Signal transduction|signaling pathways]]; they are: (1) the [[JAK-STAT signaling pathway|JAK-STAT]] pathway, (2) the [[PI3K/AKT/mTOR pathway|PI3K/Akt/mTOR]] pathway and (3) the [[MAPK/ERK pathway|MAPK/ERK]] pathway.<ref name=":0" /> The signalling is commenced by IL-2 binding to its receptor, following which cytoplasmatic domains of [[CD122]] and [[CD132]] [[heterodimerize]]. This leads to the activation of [[Janus kinase]]s [[Janus kinase 1|JAK1]] and [[Janus kinase 3|JAK3]] which subsequently [[Phosphorylation|phosphorylate]] [[Tyrosine|T338]] on CD122. This phosphorylation recruits [[Stat transcription factors|STAT transcription factors]], predominantly [[STAT5]], which dimerize and migrate to the [[cell nucleus]] where they bind to [[DNA]].<ref>{{cite journal | vauthors = Friedmann MC, Migone TS, Russell SM, Leonard WJ | title = Different interleukin 2 receptor beta-chain tyrosines couple to at least two signaling pathways and synergistically mediate interleukin 2-induced proliferation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 5 | pages = 2077–82 | date = March 1996 | pmid = 8700888 | doi = 10.1073/pnas.93.5.2077 | pmc = 39912 | bibcode = 1996PNAS...93.2077F | doi-access = free }}</ref> with an "express other proteins" signal. The proteins expressed by means of the three pathways include bcl-6 (the [[PI3K/AKT/mTOR pathway|PI3K/Akt/mTOR]] pathway), CD25 & prdm-1 (the [[JAK-STAT signaling pathway|JAK-STAT]] pathway) and certain cyclins (the [[MAPK/ERK pathway|MAPK/ERK]] pathway).

Gene expression regulation for IL-2 can be on multiple levels or by different ways. One of the checkpoints (in other words one of the things which needs to be done before IL-2 is expressed) is that there must be signaling through a conjunction of a T Cell Receptor (a TCR) and an HLA-peptide complex. As a result of that conjunction a signalling pathway (signalling a cell's protein making machinery to express or 'make' IL-2), a PhosphoLipase-C (PLC) dependent pathway, is set up. PLC activates 3 major transcription factors and their pathways: [[NFAT]], [[NFkB]] and [[AP-1 transcription factor|AP-1]]. In addition and after costimulation from CD28 the optimal activation of expression of IL-2 and these pathways is induced. In summary therefore before a cell will make IL-2 in accordance with this pathway there have to be two reactions: TCR+HLA and protein complex on the one hand and CD28 costimulation on the other indeed mere IL-2 ligation to its receptor is too low affinity to enable pathway.

At the same time [[Oct-1]] is expressed. It helps the activation. Oct1 is expressed in T-lymphocytes and [[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, [[Central tolerance|tolerance]] and [[Immunity (medical)|immunity]], primarily via its direct effects on [[T cells]]. In the [[thymus]], where T cells mature, it prevents [[autoimmune diseases]] by promoting the [[Cellular differentiation|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 enhances [[Activation-induced cell death|activation-induced cell death (AICD)]].<ref name=":0" /> 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.<ref name="Liao_2011"/> Together with other polarizing cytokines, IL-2 stimulates naive CD4<sup>+</sup> T cell differentiation into [[Th1 cell|T<sub>h</sub>1]] and [[Th2 cell|T<sub>h</sub>2]] lymphocytes while it impedes differentiation into [[T helper 17 cell|T<sub>h</sub>17]] and folicular T<sub>h</sub> lymphocytes.<ref>{{cite journal | vauthors = Liao W, Lin JX, Leonard WJ | title = Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy | journal = Immunity | volume = 38 | issue = 1 | pages = 13–25 | date = January 2013 | pmid = 23352221 | doi = 10.1016/j.immuni.2013.01.004 | pmc = 3610532 }}</ref><ref name="pmid30089912">{{cite journal | vauthors = Spolski R, Li P, Leonard WJ | title = Biology and regulation of IL-2: from molecular mechanisms to human therapy | journal = [[Nature Reviews Immunology]] | volume = 18 | issue=10 | pages = 648–659 |date=2018 | doi = 10.1038/s41577-018-0046-y | pmid = 30089912| s2cid = 51939991 }}</ref>

IL-2 increases the cell killing activity of both [[natural killer cell]]s and [[cytotoxic T cell]]s.<ref name="pmid30089912" />

Its expression and secretion is tightly regulated and functions as part of both transient positive and negative [[Feedback#Biology|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]].<ref name="Liao_2011" /><ref name="Malek_2010">{{cite journal | vauthors = Malek TR, Castro I | title = Interleukin-2 receptor signaling: at the interface between tolerance and immunity | journal = Immunity | volume = 33 | issue = 2 | pages = 153–65 | date = August 2010 | pmid = 20732639 | pmc = 2946796 | doi = 10.1016/j.immuni.2010.08.004 }}</ref>

== Evolution ==
IL-2 has been discovered in all classes of jawed vertebrates, including sharks, at a similar genomic location.<ref>{{cite journal | vauthors = Bird S, Zou J, Kono T, Sakai M, Dijkstra JM, Secombes C | title = Characterisation and expression analysis of interleukin 2 (IL-2) and IL-21 homologues in the Japanese pufferfish, Fugu rubripes, following their discovery by synteny | journal = Immunogenetics | volume = 56 | issue = 12 | pages = 909–923 | date = March 2005 | pmid = 15592926 | doi = 10.1007/s00251-004-0741-7 | s2cid = 6739341 }}</ref><ref>{{cite journal | vauthors = Dijkstra JM | title = A method for making alignments of related protein sequences that share very little similarity; shark interleukin 2 as an example | journal = Immunogenetics | volume = 73 | issue = 1 | pages = 35–51 | date = February 2021 | pmid = 33512550 | doi = 10.1007/s00251-020-01191-5 | s2cid = 231770873 }}</ref> In fish, IL-2 shares a single receptor alpha chain with its related cytokines IL-15 and [[IL-15-like]] (IL-15L).<ref name=":2">{{cite journal | vauthors = Yamaguchi T, Chang CJ, Karger A, Keller M, Pfaff F, Wangkahart E, Wang T, Secombes CJ, Kimoto A, Furihata M, Hashimoto K, Fischer U, Dijkstra JM | title = Ancient Cytokine Interleukin 15-Like (IL-15L) Induces a Type 2 Immune Response | journal = Frontiers in Immunology | volume = 11 | pages = 549319 | date = 2020-10-29 | pmid = 33193315 | pmc = 7658486 | doi = 10.3389/fimmu.2020.549319 | doi-access = free }}</ref> This "IL-15Rα" receptor chain is similar to mammalian IL-15Rα,<ref>{{cite journal | vauthors = Fang W, Shao JZ, Xiang LX | title = Molecular cloning and characterization of IL-15R alpha gene in rainbow trout (Oncorhynchus mykiss) | journal = Fish & Shellfish Immunology | volume = 23 | issue = 1 | pages = 119–127 | date = July 2007 | pmid = 17101279 | doi = 10.1016/j.fsi.2006.09.011 | bibcode = 2007FSI....23..119F }}</ref> and in tetrapod evolution a duplication of its coding gene plus further diversification created mammalian IL-2Rα.<ref>{{cite journal | vauthors = Anderson DM, Kumaki S, Ahdieh M, Bertles J, Tometsko M, Loomis A, Giri J, Copeland NG, Gilbert DJ, Jenkins NA | title = Functional characterization of the human interleukin-15 receptor alpha chain and close linkage of IL15RA and IL2RA genes | journal = The Journal of Biological Chemistry | volume = 270 | issue = 50 | pages = 29862–29869 | date = December 1995 | pmid = 8530383 | doi = 10.1074/jbc.270.50.29862 | doi-access = free }}</ref><ref name=":5">{{cite journal | vauthors = Dijkstra JM, Takizawa F, Fischer U, Friedrich M, Soto-Lampe V, Lefèvre C, Lenk M, Karger A, Matsui T, Hashimoto K | title = Identification of a gene for an ancient cytokine, interleukin 15-like, in mammals; interleukins 2 and 15 co-evolved with this third family member, all sharing binding motifs for IL-15Rα | journal = Immunogenetics | volume = 66 | issue = 2 | pages = 93–103 | date = February 2014 | pmid = 24276591 | pmc = 3894449 | doi = 10.1007/s00251-013-0747-0 }}</ref> Sequences, and structural analysis of grass carp IL-2, suggest that fish IL-2 binds IL-15Rα in a manner reminiscent of how mammalian IL-15 binds to IL-15Rα.<ref name=":5" /><ref>{{cite journal | vauthors = Wang J, Wang W, Xu J, Jia Z, Liu Q, Zhu X, Xia C, Zou J | title = Structural insights into the co-evolution of IL-2 and its private receptor in fish | journal = Developmental and Comparative Immunology | volume = 115 | pages = 103895 | date = February 2021 | pmid = 33065202 | doi = 10.1016/j.dci.2020.103895 | s2cid = 223557924 }}</ref>

Despite fish IL-2 and IL-15 sharing the same IL-15Rα chain, the stability of fish IL-2 is independent of it whereas IL-15 and especially IL-15L depend on binding to (co-presentation with) IL-15Rα for their stability and function.<ref name=":2" /> This suggests that, like in mammals, fish IL-2, in contrast to fish IL-15 and IL-15L, is not relying on "in trans" presentation by its receptor alpha chain. As a free cytokine, mammalian IL-2 that is secreted by activated T cells is important for a negative feedback loop by the stimulation of regulatory T cells, the latter being the cells with the highest constitutive IL-2Rα (aka CD25) expression.<ref name=":3">{{cite journal | vauthors = Busse D, de la Rosa M, Hobiger K, Thurley K, Flossdorf M, Scheffold A, Höfer T | title = Competing feedback loops shape IL-2 signaling between helper and regulatory T lymphocytes in cellular microenvironments | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 7 | pages = 3058–3063 | date = February 2010 | pmid = 20133667 | pmc = 2840293 | doi = 10.1073/pnas.0812851107 | bibcode = 2010PNAS..107.3058B | doi-access = free }}</ref><ref name=":4">{{cite journal | vauthors = Boyman O, Sprent J | title = The role of interleukin-2 during homeostasis and activation of the immune system | journal = Nature Reviews. Immunology | volume = 12 | issue = 3 | pages = 180–190 | date = February 2012 | pmid = 22343569 | doi = 10.1038/nri3156 | s2cid = 22680847 }}</ref> Besides this [[negative feedback]] loop, mammalian IL-2 also participates in a positive feedback loop because activated T cells enhance their own IL-2Rα expression.<ref name=":3" /><ref name=":4" /> As in mammals, fish IL-2 also stimulates T cell proliferation<ref>{{cite journal | vauthors = Corripio-Miyar Y, Secombes CJ, Zou J | title = Long-term stimulation of trout head kidney cells with the cytokines MCSF, IL-2 and IL-6: gene expression dynamics | journal = Fish & Shellfish Immunology | volume = 32 | issue = 1 | pages = 35–44 | date = January 2012 | pmid = 22051181 | doi = 10.1016/j.fsi.2011.10.016 | bibcode = 2012FSI....32...35C }}</ref> and appears to preferentially stimulate regulatory T cells.<ref>{{cite journal | vauthors = Wen Y, Fang W, Xiang LX, Pan RL, Shao JZ | title = Identification of Treg-like cells in Tetraodon: insight into the origin of regulatory T subsets during early vertebrate evolution | journal = Cellular and Molecular Life Sciences | volume = 68 | issue = 15 | pages = 2615–2626 | date = August 2011 | pmid = 21063894 | doi = 10.1007/s00018-010-0574-5 | s2cid = 22936159 | pmc = 11115099 }}</ref> Fish IL-2 induces the expression of cytokines of both type 1 (Th1) and type 2 (Th2) immunity.<ref name=":2" /><ref>{{cite journal | vauthors = Wang T, Hu Y, Wangkahart E, Liu F, Wang A, Zahran E, Maisey KR, Liu M, Xu Q, Imarai M, Secombes CJ | title = Interleukin (IL)-2 Is a Key Regulator of T Helper 1 and T Helper 2 Cytokine Expression in Fish: Functional Characterization of Two Divergent ''IL2'' Paralogs in Salmonids | journal = Frontiers in Immunology | volume = 9 | pages = 1683 | date = 2018-07-26 | pmid = 30093902 | doi = 10.3389/fimmu.2018.01683 | pmc = 6070626 | doi-access = free }}</ref>

As has been found in some studies on mammalian IL-2,<ref>{{cite journal | vauthors = Fukushima K, Hara-Kuge S, Ideo H, Yamashita K | title = Carbohydrate recognition site of interleukin-2 in relation to cell proliferation | journal = The Journal of Biological Chemistry | volume = 276 | issue = 33 | pages = 31202–31208 | date = August 2001 | pmid = 11390392 | doi = 10.1074/jbc.M102789200 | doi-access = free }}</ref> data suggest that fish IL-2 can form homodimers and that this is an ancient property of the IL-2/15/15L-family cytokines.<ref name=":2" />

Homologues of IL-2 have not been reported for jawless fish (hagfish and lamprey) or invertebrates.

== Role in disease ==

While the causes of [[pruritus|itchiness]] are poorly understood, some evidence indicates that IL-2 is involved in itchy [[psoriasis]].<ref name="pmid18288273">{{cite journal | vauthors = Reich A, Szepietowski JC | title = Mediators of pruritus in psoriasis | journal = Mediators of Inflammation | volume = 2007 | pages = 1–6 | year = 2007 | pmid = 18288273 | pmc = 2221678 | doi = 10.1155/2007/64727 | doi-access = free }}</ref>

== Medical use ==
{{Infobox drug
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=== Pharmaceutical analogues ===
[[Aldesleukin]] is a form of recombinant interleukin-2. It is manufactured using [[recombinant DNA]] technology and is marketed as a [[Biologic medical product|protein therapeutic]] and branded as Proleukin. It has been approved by the [[Food and Drug Administration]] (FDA) with a [[black box warning]] and in several European countries for the treatment of cancers ([[Melanoma|malignant melanoma]], [[Renal cell carcinoma|renal cell cancer]]) in large intermittent doses and has been extensively used in continuous doses.<ref name="pmid18031103">{{cite journal | vauthors = Noble S, Goa KL | title = Aldesleukin (recombinant interleukin-2) | journal = BioDrugs | volume = 7 | issue = 5 | pages = 394–422 | date = May 1997 | pmid = 18031103 | doi = 10.2165/00063030-199707050-00007 | s2cid = 34226322 }}</ref><ref name="pmid19544689">{{cite journal | vauthors = Bhatia S, Tykodi SS, Thompson JA | title = Treatment of metastatic melanoma: an overview | journal = Oncology | volume = 23 | issue = 6 | pages = 488–96 | date = May 2009 | pmid = 19544689 | pmc = 2737459 | url = http://www.cancernetwork.com/oncology-journal/treatment-metastatic-melanoma-overview }}</ref><ref name=Pollack_1990/>

Interking is a recombinant IL-2 with a [[serine]] at residue 125, sold by Shenzhen Neptunus.<ref>{{cite web | work = Bloomberg BusinessWeek | date = 3 March 2014 | url = http://investing.businessweek.com/research/stocks/snapshot/snapshot.asp?ticker=8329:HK | archive-url = https://web.archive.org/web/20110227091103/http://investing.businessweek.com/research/stocks/snapshot/snapshot.asp?ticker=8329:HK | url-status = dead | archive-date = February 27, 2011 | title = Shenzhen Neptunus Interlng-H }}</ref>

Neoleukin 2/15 is a computationally designed mimic of IL-2 that was designed to avoid common side effects.<ref>{{cite journal | vauthors = Silva DA, Yu S, Ulge UY, Spangler JB, Jude KM, Labão-Almeida C, Ali LR, Quijano-Rubio A, Ruterbusch M, Leung I, Biary T, Crowley SJ, Marcos E, Walkey CD, Weitzner BD, Pardo-Avila F, Castellanos J, Carter L, Stewart L, Riddell SR, Pepper M, Bernardes GJ, Dougan M, Garcia KC, Baker D | title = De novo design of potent and selective mimics of IL-2 and IL-15 | journal = Nature | volume = 565 | issue = 7738 | pages = 186–191 | date = January 2019 | pmid = 30626941 | doi = 10.1038/s41586-018-0830-7 | pmc = 6521699 | bibcode = 2019Natur.565..186S }}</ref> However, clinical trials into this candidate were discontinued.<ref>{{cite web |url=https://www.biospace.com/article/neoleukin-therapeutics-slashes-workforce-drops-de-novo-protein-therapeutic-/|title= Neoleukin Drops de Novo Protein Therapeutic, Slashes Workforce - Updated|vauthors = Scott R |date=November 15, 2022 |website=BioSpace |publisher= |access-date= February 1, 2023}}</ref>

==== Dosage ====
Various dosages of IL-2 across the [[United States]] and across the world are used. The efficacy and [[side effect]]s of different dosages is often a point of disagreement.

The commercial interest in local IL-2 therapy has been very low. Because only a very low dose IL-2 is used, treatment of a patient would cost about $500 commercial value of the patented IL-2. The commercial return on investment is too low to stimulate additional clinical studies for the registration of intratumoral IL-2 therapy.

===== 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.<ref name="American Cancer Society">American Cancer Society. [http://www.cancer.org/Treatment/TreatmentsandSideEffects/GuidetoCancerDrugs/INTERLEUKIN-2 Interleukin-2 (Aldesleukin)] {{Webarchive|url=https://web.archive.org/web/20150212072442/http://www.cancer.org/treatment/treatmentsandsideeffects/guidetocancerdrugs/interleukin-2 |date=2015-02-12 }}. Date accessed: 07 Nov 10.</ref>

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]].<ref name="American Cancer Society" />

Intralesional IL-2 is commonly used to treat in-transit melanoma metastases and has a high complete response rate.<ref name="Intralesional_IL_2">{{cite journal | vauthors = 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 | title = 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 = Journal of the American Academy of Dermatology | volume = 73 | issue = 4 | pages = 645–54 | date = October 2015 | pmid = 26259990 | doi = 10.1016/j.jaad.2015.06.060 | doi-access = free }}</ref>

==== Local application ====
In preclinical and early clinical studies, local application of IL-2 in the tumor has been shown to be clinically more effective in anticancer therapy than systemic IL-2 therapy, over a broad range of doses, without serious side effects.<ref name="pmid18256831 ">{{cite journal | vauthors = Den Otter W, Jacobs JJ, Battermann JJ, Hordijk GJ, Krastev Z, Moiseeva EV, Stewart RJ, Ziekman PG, Koten JW | title = Local therapy of cancer with free IL-2 | journal =  Cancer Immunology, Immunotherapy| volume = 57 | issue = 7 | pages = 931–50 | date = July 2008 | pmid = 18256831 | pmc = 2335290 | doi = 10.1007/s00262-008-0455-z }}</ref>

Tumour blood vessels are more vulnerable than normal blood vessels to the actions of IL-2. When injected inside a tumor, i.e. local application, a process mechanistically similar to the vascular leakage syndrome, occurs in tumor tissue only. Disruption of the blood flow inside of the tumor effectively destroys tumor tissue.<ref name="pmid15685449  ">{{cite journal | vauthors = Jacobs JJ, Sparendam D, Den Otter W | title = Local interleukin 2 therapy is most effective against cancer when injected intratumourally | journal =  Cancer Immunology, Immunotherapy| volume = 57 | issue = 7 | pages = 931–50 | date = July 2005 | pmid = 15685449 | doi = 10.1007/s00262-004-0627-4 | s2cid = 41522233 | pmc = 11033014 }}</ref>

In local application, the systemic dose of IL-2 is too low to cause side effects, since the total dose is about 100 to 1000 fold lower. Clinical studies showed painful injections at the site of radiation as the most important side effect, reported by patients. In the case of irradiation of nasopharyngeal carcinoma the five-year disease-free survival increased from 8% to 63% by local IL-2 therapy <ref name="pmid15627211 ">{{cite journal | vauthors = Jacobs JJ, Hordijk GJ, Jürgenliemk-Schulz IM, Terhaard CH, Koten JW, Battermann JJ, Den Otter W | title = Treatment of stage III-IV nasopharyngeal carcinomas by external beam irradiation and local low doses of IL-2 | journal =  Cancer Immunol Immunother| volume = 57 | issue = 8 | pages = 792–8 | date = August 2005 | pmid = 15685449 | doi = 10.1007/s00262-004-0627-4 | s2cid = 41522233 | pmc = 11033014 }}</ref>

====Toxicity====
Systemic IL-2 has a narrow [[therapeutic window]], and the level of dosing usually determines the severity of the side effects.<ref name="pmid19009549">{{cite journal | vauthors = Shaker MA, Younes HM | title = Interleukin-2: evaluation of routes of administration and current delivery systems in cancer therapy | journal = Journal of Pharmaceutical Sciences | volume = 98 | issue = 7 | pages = 2268–98 | date = July 2009 | pmid = 19009549 | doi = 10.1002/jps.21596 }}</ref> In the case of local IL-2 application, the therapeutic window spans several orders of magnitude.<ref name="pmid18256831"/>

Some common side effects:<ref name="American Cancer Society" />
* [[flu]]-like symptoms ([[fever]], [[headache]], [[Muscle pain|muscle]] and [[joint pain]], [[fatigue (medical)|fatigue]])
* [[nausea]]/[[vomiting]]
* dry, itchy skin or [[rash]]
* [[weakness]] or [[shortness of breath]]
* [[diarrhea]]
* [[Hypotension|low blood pressure]]
* [[drowsiness]] or [[confusion]]
* [[loss of appetite]]

More serious and dangerous side effects sometimes are seen, such as [[breathing]] problems, serious [[infection]]s, [[seizure]]s, [[allergic reaction]]s, [[heart]] problems, [[kidney failure]] or a variety of other possible complications.<ref name="American Cancer Society" /> The most common adverse effect of high-dose IL-2 therapy is vascular leak syndrome (VLS; also termed [[capillary leak syndrome]]). It is caused by lung endothelial cells expressing high-affinity IL-2R. These cells, as a result of IL-2 binding, causes increased vascular permeability. Thus, intravascular fluid extravasate into organs, predominantly lungs, which leads to life-threatening pulmonary or brain oedema.<ref>{{Cite journal|date=2011-12-28|title=Correction for Krieg et al., Improved IL-2 immunotherapy by selective stimulation of IL-2 receptors on lymphocytes and endothelial cells|journal=Proceedings of the National Academy of Sciences|volume=109|issue=1|pages=345|doi=10.1073/pnas.1119897109|issn=0027-8424|pmc=3252892|doi-access=free}}</ref>

Other drawbacks of IL-2 cancer immunotherapy are its short half-life in circulation and its ability to predominantly expand regulatory T cells at high doses.<ref name=":0" /><ref name="Liao_2011" />

Intralesional IL-2 used to treat in-transit melanoma metastases is generally well tolerated.<ref name="Intralesional_IL_2"/> This is also the case for intralesional IL-2 in other forms of cancer, like nasopharyngeal carcinoma.<ref name="pmid15627211"/>

=== 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]].<ref>{{cite journal | vauthors = Figgitt DP, Lamb HM, Goa KL | title = Denileukin diftitox | journal = American Journal of Clinical Dermatology | volume = 1 | issue = 1 | pages = 67–72; discussion 73 | date = 2000 | pmid = 11702307 | doi =  10.2165/00128071-200001010-00008| s2cid = 195358361 }}</ref> 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 [[Food and Drug Administration|U.S. Food and Drug Administration]] (FDA) for treatment of [[cutaneous T cell lymphoma]] (CTCL).<ref>{{cite web | publisher = FDA | date = May 11, 2009 | url = https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm095661.htm | archive-url = https://web.archive.org/web/20111125071549/http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm095661.htm | url-status = dead | archive-date = November 25, 2011 | title = Changes in the Ontak (denileukin diftitiox) | work = Package Insert to Include a Description of Ophthalmologic Adverse Events }}</ref>

== Preclinical research ==
IL-2 does not follow the classical dose-response curve of chemotherapeutics. The immunological activity of high and low dose IL-2 show sharp contrast. This might be related to different distribution of IL-2 receptors (CD25, CD122, CD132) on different cell populations, resulting in different cells that are activated by high and low dose IL-2. In general high doses are immune suppressive, while low doses can stimulate type 1 immunity.<ref>{{cite journal | vauthors = Tomova R, Pomakov J, Jacobs JJ, Adjarov D, Popova S, Altankova I, Den Otter W, Krastev Z | title = Changes in cytokine profile during local IL-2 therapy in cancer patients | journal = Anticancer Research | volume = 26 | issue = 3A | pages = 2037–47 | date = May–June 2006 | pmid = 16827142  }}</ref> Low-dose IL-2 has been reported to reduce hepatitis C and B infection.<ref>{{cite journal | vauthors = Tomova R, Antonov K, Ivanova A, Jacobs JJ, Koten JW, Den Otter W, Krastev Z | title = CLow-dose IL-2 therapy reduces HCV RNA and HBV DNA: case report. | journal = Anticancer Research | volume = 29 | issue = 12 | pages = 5241–4 | date = December 2009 | pmid = 20044643}}</ref>

IL-2 has been used 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 [[HIV/AIDS|AIDS]] diagnosis in two large clinical trials published in 2009.<ref>{{cite web | url = http://www.nih.gov/news/health/feb2009/niaid-10.htm | title = IL-2 Immunotherapy Fails to Benefit HIV-Infected Individuals Already Taking Antiretrovirals | date = February 10, 2009 | work = News Release | publisher = National Institutes of Health (NIH) }}</ref>

More recently low dose IL-2 has shown early success in modulating the immune system in disease like type 1 diabetes and vasculitis.<ref>{{cite journal | vauthors = Hartemann A, Bensimon G, Payan CA, Jacqueminet S, Bourron O, Nicolas N, Fonfrede M, Rosenzwajg M, Bernard C, Klatzmann D | title = Low-dose interleukin 2 in patients with type 1 diabetes: a phase 1/2 randomised, double-blind, placebo-controlled trial | journal = The Lancet. Diabetes & Endocrinology | volume = 1 | issue = 4 | pages = 295–305 | date = December 2013 | pmid = 24622415 | doi = 10.1016/S2213-8587(13)70113-X }}</ref> There are also promising studies looking to use low dose IL-2 in ischaemic heart disease.<ref>{{ClinicalTrialsGov|NCT03113773|Low Dose Interleukin-2 in Patients With Stable Ischaemic Heart Disease and Acute Coronary Syndromes (LILACS)}}</ref>

=== IL-2/anti-IL-2 mAb immune complexes (IL-2 ic) ===
IL-2 cannot accomplish its role as a promising [[Immunotherapy|immunotherapeutic]] agent due to significant drawbacks which are listed above. Some of the issues can be overcome using IL-2 ic. They are composed of IL-2 and some of its [[monoclonal antibody]] (mAb) and can potentiate biologic activity of IL-2 ''[[in vivo]]''. The main mechanism of this phenomenon ''in vivo'' is due to the prolongation of the [[cytokine]] half-life in circulation. Depending on the clone of IL-2 mAb, IL-2 ic can selectively stimulate either CD25<sup>high</sup> (IL-2/JES6-1 complexes), or CD122<sup>high</sup> cells (IL-2/S4B6). IL-2/S4B6 immune complexes have high stimulatory activity for [[Natural killer cell|NK cells]] and memory [[Cytotoxic T cell|CD8<sup>+</sup> T cells]] and they could thus replace the conventional IL-2 in [[cancer immunotherapy]]. On the other hand, IL-2/JES6-1 highly selectively stimulate [[regulatory T cell]]s and they could be potentially useful for [[Organ transplantation|transplantations]] and in treatment of [[autoimmune disease]]s.<ref>{{cite journal | vauthors = Boyman O, Kovar M, Rubinstein MP, Surh CD, Sprent J | title = Selective stimulation of T cell subsets with antibody-cytokine immune complexes | journal = Science | volume = 311 | issue = 5769 | pages = 1924–7 | date = March 2006 | pmid = 16484453 | doi = 10.1126/science.1122927 | bibcode = 2006Sci...311.1924B | s2cid = 42880544 | doi-access = free }}</ref><ref name=":0" />

== 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".<ref name="Leonard"/>{{rp|712}}

In the mid-1960s, studies reported "activities" in leukocyte-conditioned media that promoted [[lymphocyte]] proliferation.<ref name="pmid20074271">{{cite journal | vauthors = Chavez AR, Buchser W, Basse PH, Liang X, Appleman LJ, Maranchie JK, Zeh H, de Vera ME, Lotze MT | title = Pharmacologic administration of interleukin-2 | journal = Annals of the New York Academy of Sciences | volume = 1182 | issue =  1| pages = 14–27 | date = December 2009 | pmid = 20074271 | doi = 10.1111/j.1749-6632.2009.05160.x | bibcode = 2009NYASA1182...14C | s2cid = 1100312 }}</ref>{{rp|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.<ref name="Leonard">{{cite book | vauthors = Paul WE | title = Fundamental immunology | date = 2008 | publisher = Wolters Kluwer/Lippincott Williams & Wilkins | location = Philadelphia | isbn = 978-0-7817-6519-0 | edition = 6th }}</ref>{{rp|712}} The key factor was isolated from cultured mouse cells in 1979 and from cultured human cells in 1980.<ref name="pmid6980256">{{cite journal | vauthors = Welte K, Wang CY, Mertelsmann R, Venuta S, Feldman SP, Moore MA | title = Purification of human interleukin 2 to apparent homogeneity and its molecular heterogeneity | journal = The Journal of Experimental Medicine | volume = 156 | issue = 2 | pages = 454–64 | date = August 1982 | pmid = 6980256 | pmc = 2186775 | doi = 10.1084/jem.156.2.454 }}</ref> The gene for human IL-2 was cloned in 1982 after an intense competition.<ref name=CetusHist>{{cite book | vauthors = Rabinow P | title = Making PCR: A story of biotechnology | url = https://archive.org/details/makingpcrstoryof00rabi | url-access = registration | year = 1997 | publisher = University of Chicago Press | location = Chicago, IL, USA | isbn = 978-0226701479 | edition = Paperback }}</ref>{{rp|76}}

Commercial activity to bring an IL-2 drug to market was intense in the 1980s and 1990s. 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.<ref name=CetusHist/>{{rp|76–77}}<ref>{{cite journal | vauthors = Almeida H | url = http://www.scielo.br/pdf/bjps/v47n2/v47n2a02.pdf | title = Drugs obtained by biotechnology processing | journal = Brazilian Journal of Pharmaceutical Sciences | date = April–June 2011 | volume = 47 | issue = 2 | pages = 199–207 | doi=10.1590/s1984-82502011000200002| doi-access = free }}</ref>{{rp|201}}<ref name="Whittington_1993"/> [[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.<ref name=CetusHist/>{{rp|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.<ref name="Pollack_1990">{{cite web |url= https://www.nytimes.com/1990/07/31/business/cetus-drug-is-blocked-by-fda.html |title=Cetus Drug Is Blocked By F.D.A. |work=New York Times |author=Pollack A |date=July 31, 1990}} This source mentions approval in 9 European countries.</ref> The failure led to the collapse of Cetus, and in 1991 the company was sold to [[Chiron Corporation]].<ref name="Pollack_1991">{{cite web | vauthors = Pollack A | url = https://www.nytimes.com/1991/07/23/business/2-biotech-pioneers-to-merge.html | title = 2 Biotech Pioneers To Merge |work=New York Times | date = July 23, 1991 }}</ref><ref name="Lehrman_1992">{{cite web | vauthors = Lehrman S | url = http://www.the-scientist.com/?articles.view/articleNo/12113/title/Cetus–A-Collision-Course-With-Failure/ |title=Cetus: A Collision Course With Failure |work=The Scientist Magazine | date = January 20, 1992 }}</ref> Chiron continued the development of IL-2, which was finally approved by the FDA as Proleukin for metastatic [[renal carcinoma]] in 1992.<ref name="pmid12469934">{{cite journal | vauthors = Dutcher JP | title = Current status of interleukin-2 therapy for metastatic renal cell carcinoma and metastatic melanoma | journal = Oncology | volume = 16 | issue = 11 Suppl 13 | pages = 4–10 | date = November 2002 | pmid = 12469934 }}</ref>

By 1993 aldesleukin was the only approved version of IL-2, but [[Hoffmann-La Roche|Roche]] was also developing a proprietary, modified, recombinant IL-2 called teceleukin, with a [[methionine]] added at is N-terminal, and [[GlaxoSmithKline|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.<ref name="Whittington_1993">{{cite journal | vauthors = Whittington R, Faulds D | title = Interleukin-2. A review of its pharmacological properties and therapeutic use in patients with cancer | journal = Drugs | volume = 46 | issue = 3 | pages = 446–514 | date = September 1993 | pmid = 7693434 | doi = 10.2165/00003495-199346030-00009 | s2cid = 209143485 }}</ref><ref name="urlKEGG DRUG: D02749">{{cite web |url=http://www.genome.jp/dbget-bin/www_bget?dr:D02749 |title=D02749 (Teceleukin) |work=KEGG drug }}</ref> [[Novartis]] acquired Chiron in 2006<ref name="urlChiron shareholders approve Novartis deal - SWI swissinfo.ch">{{cite web |url=http://www.swissinfo.ch/eng/chiron-shareholders-approve-novartis-deal/5134216 |title=Chiron shareholders approve Novartis deal |work=SWI swissinfo.ch |date=Apr 19, 2006}}</ref> and licensed the US aldesleukin business to Prometheus Laboratories in 2010<ref name="urlNovartis sells rights to Proleukin in the USA to Prometheus; gets license for vaccine from IIG; and pleads guilty over Trileptal">{{cite web |url=http://www.thepharmaletter.com/article/novartis-sells-rights-to-proleukin-in-the-usa-to-prometheus-gets-license-for-vaccine-from-iig-and-pleads-guilty-over-trileptal |title=Novartis sells rights to Proleukin in the USA to Prometheus; gets license for vaccine from IIG; and pleads guilty over Trileptal |work=Pharmaletter |date=January 27, 2010}}</ref> before global rights to Proleukin were subsequently acquired by Clinigen in 2018 and 2019.

== References ==
{{reflist|33em}}

== External links ==
{{commons category|Interleukin-2}}
* [http://www.proleukin.com Proleukin website]
* [http://www.netpath.org/pathways?path_id=NetPath_14 IL-2 Signaling Pathway] {{Webarchive|url=https://web.archive.org/web/20200111235452/http://www.netpath.org/pathways?path_id=NetPath_14 |date=2020-01-11 }}
* {{cite journal | vauthors = Rosenberg SA | title = IL-2: the first effective immunotherapy for human cancer | journal = Journal of Immunology | volume = 192 | issue = 12 | pages = 5451–8 | date = June 2014 | pmid = 24907378 | pmc = 6293462 | doi = 10.4049/jimmunol.1490019 }}
* {{PDBe-KB2|P60568|Interleukin-2}}

{{PDB_Gallery|geneid=3558}}
{{Interleukins}}
{{Interleukin receptor modulators}}

[[Category:Interleukins]]
[[Category:Immunostimulants]]
[[Category:Cancer treatments]]
[[Category:Immunomodulating drugs]]
[[Category:Immunology]]