Human Interleukin 2 crystal structure
|Symbols||; IL-2; TCGF; lymphokine|
|External IDs||ChEMBL: GeneCards:|
|RNA expression pattern|
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.
IL-2 is a member of a cytokine family that also includes IL-4, IL-7, IL-9, IL-15 and IL-21. IL-2 signals through a receptor complex consisting of three chains, termed alpha, beta and gamma. The gamma chain is shared by all members of this family of cytokine receptors.
IL-2 is necessary for the growth, proliferation, and differentiation of thymic-derived lymphocytes (T cells) to become 'effector' T cells. IL-2 is normally produced by T cells during an immune response. Antigen binding to the T cell receptor (TCR) stimulates the secretion of IL-2, and the expression of IL-2 receptors IL-2R. The IL-2/IL-2R interaction then stimulates the growth, differentiation and survival of antigen-specific CD4+ T cells and CD8+ T cells As such, IL-2 is necessary for the development of T cell immunologic memory, which depends upon the expansion of the number and function of antigen-selected T cell clones.
IL-2 is also necessary during T cell development in the thymus for the maturation of a subset of T cells that are termed regulatory T cells (T-regs). After exiting from the thymus, T-Regs function to prevent other T cells from recognizing and reacting against self antigens, which could result in autoimmunity. T-Regs do so by preventing the responding cells from producing IL-2. Also, because T-Reg cells constitutively express IL-2 receptors, they bind, internalize, and degrade IL-2, thereby depriving neighboring effector T cells of IL-2. Thus, IL-2 is required to discriminate between self and non-self, one of the other hallmarks of the immune system.
IL-15 was found to be similar to IL-2. Both cytokines are able to facilitate production of immunoglobulins made by B cells and induce the differentiation and proliferation of natural killer cells. The primary differences between IL-2 and IL-15 are found in adaptive immune responses. For example, IL-2 is necessary for adaptive immunity to foreign pathogens, as it is the basis for the development of immunological memory. On the other hand, IL-15 is necessary for maintaining highly specific T cell responses by supporting the survival of CD8 memory T cells
IL-2 has a well-documented role in induction of pruritus. Direct injection of this cytokine into skin of healthy subjects as well as those with atopic dermatitis has resulted in itching. Furthermore, it has been found to be higher in pruritic lesions of psoriasis compared to non-pruritic ones. Serum levels of IL-2 have been demonstrated to be higher in hemodialysis patients with itch (uremic pruritus) compared to those without itch. As a proof, therapeutic measures that inhibit IL-2 such as Ultraviolet therapy, tacrolimus, and thalidomide have been demonstrated to be effective in treatment of uremic pruritus.
Many of the immunosuppressive drugs used in the treatment of autoimmune diseases and the suppression of graft rejection, such as corticosteroids, cyclosporin, and tacrolimus work by inhibiting the production of IL-2 by antigen-activated T cells. Others (sirolimus) block IL-2R signaling, thereby preventing the clonal expansion and function of antigen-selected T cells. These immunosuppressive drugs have been essential for the widespread use of organ transplants in medicine today. Without them, organs transplanted between unrelated individuals would be universally rejected.
IL-2 is manufactured using recombinant DNA technology and is marketed as a protein therapeutic called Proleukin by Prometheus Laboratories, Inc. It has been approved by the Food and Drug Administration (FDA) for the treatment of cancers (malignant melanoma, renal cell cancer) in large intermittent toxic doses.
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, toxic doses of IL-2 given every 6–8 weeks in HIV therapy, similar to its use in cancer therapy, has been found recently to be ineffective in preventing progression to an AIDS diagnosis in two large clinical trials.
IL-2, a soluble hormone-like mediator of the immune system, was the first interleukin molecule identified and characterized. Before the discovery of the IL-2 molecule and the interleukin family of molecules, which now number 37, the immune system was thought to regulated entirely from without via foreign molecules (antigens) that gained entrance to the body. Prior to the discovery of the IL-2 molecule, studies describing "activities" in leukocyte conditioned media that promoted lymphocyte proliferation were first reported simultaneously by Shinpei Kasakura and Louis Lowenstein and Julius Gordon and Lloyd MacLean in 1965 in the culture media of mixed leukocytes and were named Blastogenic Factor (BF). Between 1965 and the mid-1970s a myriad of activities, each given a different name, were found in media conditioned by leukocytes in culture. After the biochemical and genetic characteristics of IL-2 became known, Shinpei Kasakura's group performed a series of experiments defining BF almost twenty years after its first description. He was able to show that BF was distinct from IL-2, B cell growth factor and IL-1. The major distinguishing characteristic was that BF was mitogenic for unstimulated lymphocytes, whereas IL-2 mitogenic activity required prior antigenic activation to stimulate the expression of IL-2Rs. Thus, BF was probably equivalent to IL-15, which was not discovered until three years later.
Kendall Smith's group discovered the IL-2 molecule, first purifying it to homogeneity from leukocyte conditioned media, thereby demonstrating that all of the activity in the media was attributable to a single 15,500 Dalton glycoprotein. Smith was also first to show that IL-2 mediates its effects via a specific IL-2 receptor, and it was also the first interleukin molecule to be cloned and expressed from a complementary DNA (cDNA) library by Tadatsugu Taniguchi's group. Thus, despite being designated the number 2 interleukin molecule, it was the first interleukin molecule, receptor, and gene to be discovered. It was designated the number 2 interleukin molecule because Smith found that IL-1, produced by macrophages, facilitates IL-2 molecule production by T lymphocytes (T cells). These data served as the scientific rationale for the creation of the interleukin nomenclature, anticipating that more molecules would be discovered.
In popular culture
In season 5 (2009-2010) of the American medical drama television show, Grey's Anatomy, one of the main characters, surgical resident Dr. Isobel "Izzie" Stevens, is diagnosed with stage IV melanoma that has spread to other parts of her body, including her brain. She is treated with surgery and IL-2. However a USA Today article states: "'...doctors never recommend IL-2 for melanoma that has spread to the brain because it can cause bleeding and strokes', says Otis Brawley, chief medical officer at the American Cancer Society. 'If doctors are concerned about the risks of surgery, they recommend radiosurgery, in which doctors focus intensive radiation on the tumor.'"
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- NIH staff for NIH News. February 10, 2009 IL-2 Immunotherapy Fails to Benefit HIV-Infected Individuals Already Taking Antiretrovirals
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- Liz Szabo for USA TODAY. May 18, 2009 Doctors, patients say 'Grey's' cancer story isn't accurate
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