Interleukin 2

IL2
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1IRL, 1M47, 1M48, 1M49, 1M4A, 1M4B, 1M4C, 1NBP, 1PW6, 1PY2, 1QVN, 1Z92, 2B5I, 2ERJ, 3QAZ, 3QB1, 3INK, 4NEJ, 4NEM
Identifiers
Aliases	IL2, IL-2, TCGF, lymphokine, interleukin 2
External IDs	OMIM: 147680 MGI: 96548 HomoloGene: 488 GeneCards: IL2
Genetically Related Diseases
type I hypersensitivity, type 1 diabetes mellitus[1]
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 Cellular component • cytosol • extracellular space • extracellular region • cell • intracellular 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 • positive regulation of tyrosine phosphorylation of Stat5 protein • 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 Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	3558	16183
Ensembl	ENSG00000109471	ENSMUSG00000027720
UniProt	P60568	P04351
RefSeq (mRNA)	NM_000586	NM_008366
RefSeq (protein)	NP_000577.2	NP_032392.1
Location (UCSC)	Chr 4: 122.45 – 122.46 Mb	Chr 3: 37.12 – 37.13 Mb
PubMed search	[2]	[3]
Wikidata

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.

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 members of this family of cytokine receptors.^[4]

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 the signalling in T cells.^[5]

Function

IL-2 has key 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.^[4] Its expression and secretion is tightly regulated and functions as part of both transient positive and negative feedback loops in mounting immune responses and dampening them down. 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 also has a key role in enduring cell-mediated immunity.^[4][6]

Role in disease

While the causes of itchiness are poorly understood, there is some evidence that IL-2 may be involved in itchy psoriasis.^[7]

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.^[8][9][10]

Interking is a recombinant IL-2 with a serine at residue 125, sold by the Hong Kong company, Shenzhen Neptunus.^[11]

Dosages

There are different dosages of IL-2 across the United States and across the world being used to treat patients. The efficiency and side effects of different dosages is often a point of disagreement. Usually, in the U.S., the higher dosage option is used, depending on the cancer, response to treatment, and general health of the patient. Patients are typically given the high dosages for five consecutive days, three times a day, for fifteen minutes. The patient is given approximately 10 days to recover between treatment dosages. IL-2 is delivered intravenously for this type of dosing, and administration at hospital is generally required to enable proper monitoring of side effects.^[12]

Another dosage option is in a lower regimen used by some doctors. It can be an injection of IL-2 under the skin at home or doctor’s office. It is also possible to get this dosage through an IV in the hospital over 1–3 days, similar to and often including the delivery of chemotherapy.^[12]

Intralesional IL-2 is commonly used to treat in-transit melanoma metastases and has a high complete response rate.^[13]

Toxicity

IL-2 has a narrow therapeutic window, and the level of dosing usually determines the severity of the side effects.^[14]

Some common side effects:^[12]

• 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.^[12]

Intralesional IL-2 used to treat in-transit melanoma metastases is generally well-tolerated.^[13]

Pharmaceutical derivative

Eisai markets a drug called denileukin diftitox (trade name Ontak), which is recombinant fusion protein of the human IL-2 ligand and the diphtheria toxin.^[15] 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).^[16]

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.^[17]

Discovery and development

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".^[18]:712

In the mid-1960s, studies reported "activities" in leukocyte conditioned media that promoted lymphocyte proliferation.^[19]: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.^[18]:712 The key factor was isolated from cultured mouse cells in 1979 and from cultured human cells in 1980.^[20] The gene for human IL-2 was cloned in 1982 after an intense competition.^[21]: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.^{[21]:76–77[22]:201[23]} 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.^[21]: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.^[10] The failure led to the collapse of Cetus, and in 1991 the company was sold to Chiron Corporation.^[24][25] Chiron continued the development of IL-2, which was finally approved by the FDA as Proleukin for metastatic renal carcinoma in 1992.^[26] 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, and 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 infused back into the patients.^[23][27] Novartis acquired Chiron in 2006^[28] and sold the aldesleukin business to Prometheus Laboratories in 2010.^[13]

^[29]

References

External links

Wikimedia Commons has media related to Interleukin-2.

• Proleukin website
• IL-2 Signaling Pathway

PDB gallery
1irl: THE SOLUTION STRUCTURE OF THE F42A MUTANT OF HUMAN INTERLEUKIN 2  1m47: Crystal Structure of Human Interleukin-2  1m48: Crystal Structure of Human IL-2 Complexed with (R)-N-[2-[1-(Aminoiminomethyl)-3-piperidinyl]-1-oxoethyl]-4-(phenylethynyl)-L-phenylalanine methyl ester  1m49: Crystal Structure of Human Interleukin-2 Complexed with SP-1985  1m4a: Crystal Structure of Human Interleukin-2 Y31C Covalently Modified at C31 with (1H-Indol-3-yl)-(2-mercapto-ethoxyimino)-acetic acid  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  1m4c: Crystal Structure of Human Interleukin-2  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  1pw6: Low Micromolar Small Molecule Inhibitor of IL-2  1py2: Structure of a 60 nM Small Molecule Bound to a Hot Spot on IL-2  1qvn: Structure of SP4160 Bound to IL-2 V69A  1z92: structure of interleukin-2 with its alpha receptor  2b5i: cytokine receptor complex  2erj: Crystal structure of the heterotrimeric interleukin-2 receptor in complex with interleukin-2  3ink: UNRAVELING THE STRUCTURE OF INTERLEUKIN-2: REPLY