Interleukin 2

Interleukin 2
250px Human Interleukin 2 crystal structure
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1ILM, 1ILN, 1IRL, 1M47, 1M48, 1M49, 1M4A, 1M4B, 1M4C, 1NBP, 1PW6, 1PY2, 1QVN, 1Z92, 2B5I, 2ERJ, 3INK, 3QAZ, 3QB1, 4NEJ, 4NEM
Identifiers
Symbols	IL2 ; IL-2; TCGF; lymphokine
External IDs	OMIM: 147680 MGI: 96548 HomoloGene: 488 ChEMBL: 5880 GeneCards: IL2 Gene
Gene ontology Molecular function • cytokine activity • interleukin-2 receptor binding • growth factor activity • kinase activator activity • carbohydrate binding • kappa-type opioid receptor binding • glycosphingolipid binding Cellular component • extracellular region • extracellular space • cytosol Biological process • negative regulation of protein phosphorylation • negative regulation of B cell apoptotic process • immune response • cell adhesion • positive regulation of cytosolic calcium ion concentration • protein kinase C-activating G-protein coupled receptor signaling pathway • cell-cell signaling • positive regulation of cell proliferation • natural killer cell activation • T cell differentiation • positive regulation of cell growth • positive regulation of B cell proliferation • positive regulation of interferon-gamma production • positive regulation of interleukin-17 production • positive regulation of tissue remodeling • positive regulation of activated T cell proliferation • positive regulation of tyrosine phosphorylation of Stat5 protein • negative regulation of apoptotic process • positive regulation of regulatory T cell differentiation • negative regulation of heart contraction • positive regulation of transcription from RNA polymerase II promoter • regulation of T cell homeostatic proliferation • positive regulation of isotype switching to IgG isotypes • negative regulation of lymphocyte proliferation • negative regulation of inflammatory response • positive regulation of inflammatory response • positive regulation of immunoglobulin secretion • positive regulation of dendritic spine development • extrinsic apoptotic signaling pathway in absence of ligand Sources: Amigo / QuickGO
RNA expression pattern
File:PBB GE IL2 207849 at tn.png
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	NP_032392
Location (UCSC)	Chr 4: 122.45 – 122.46 Mb	Chr 3: 37.12 – 37.13 Mb
PubMed search	[1]	[2]

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.

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.

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. Its expression and secretion is tightly regulated and functions as part of both transient positive and negative feedback loops in mounting immune responses and tamping 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.

Role in disease

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

Medical use

IL-2 is manufactured using recombinant DNA technology and is marketed as a protein therapeutic called aldesleukin (branded as Proleukin) by Prometheus Laboratories, Inc. 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.

The Hong Kong company, Shenzhen Neptunus Interlng-H, sells a recombinant IL-2 called Interking, with a serine at residue 125.

Eisai sells a drug called denileukin diftitox (trade name Ontak), which is recombinant protein combining IL-2 and diphtheria toxin. 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).

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. The IL-2 is delivered through an IV for this type of dosing, and hospitalization/intensive care is required throughout due to the side effects.

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.

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

Toxicity

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

Some Common Side Effects:

• 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.

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

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.

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".

In the mid-1960s, studies reported "activities" in leukocyte conditioned media that promoted lymphocyte proliferation. 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. The key factor was isolated from cultured mouse cells in 1979 and from cultured human cells in 1980. The gene for human IL-2 was cloned in 1982 after an intense competition.

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 IL2 (aldesleukin, later called Proleukin), with the alanine removed from its N-terminal and residue 125 replaced with serine. 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. 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. The failure led to the collapse of Cetus, and in 1991 the company was sold to Chiron Corporation. Chiron continued the development of IL-2, which was finally approved by the FDA as Proleukin for metastatic renal carcinoma in 1992. 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. Novartis acquired Chiron in 2006 and sold the aldesleukin business to Prometheus Laboratories in 2010.

External links

• Proleukin website
• IL-2 Signaling Pathway