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Proleukin

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Proleukin

Interleukin 2

Human Interleukin 2 crystal structure
Available structures
PDB Ortholog search: RCSB
Identifiers
IL2 Gene
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.

History

IL-2, a soluble hormone-like mediator of the immune system, was the first interleukin identified and characterized. IL-2 was discovered in the laboratory of Robert C. Gallo by Doris Morgan, Frank Ruscetti and Gallo.[1][2] Morgan was a first year post-doctoral fellow in Gallo's lab and Ruscetti a more senior co-worker. It was initially called T cell growth factor, but the name was changed in 1978 to IL-2 (interleukin-2) by the Interlaken cytokine nomenclature committee.[3] The discovery was later confirmed by Gillis et al.[4] The discovery of IL-2 allowed T cells, previously thought to be dead end cells, to be grown significantly in culture for the first time, opening research into many aspects of T cell immunology. Gallo’s lab later purified and biochemically characterized IL-2.[5]

Previous studies that described soluble activities that were blastogenic for lymphocytes were reported simultaneously by Shinpei Kasakura and Louis Lowenstein [6] and Julius Gordon and Lloyd MacLean [7] in 1965 in the culture media of mixed leukocytes and were named Blastogenic Factor (BF). These factors and their activities were not well characterized, growth of lymphocytes was not shown, and, of course, the kind of target lymphocyte was unclear because T and B cells had not yet been defined. However, their publication was the first indication that the immune system might be regulated by soluble factors other than immunoglobulins. Between 1965 and the mid-1970s myriad soluble "activities", each given a different name, were reported in the media conditioned by leukocytes in culture. After the biochemistry 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.[8] 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 showed IL-2 to mediate its effects via a specific IL-2 receptor,[9] and it was also the first interleukin to be cloned and expressed from a complementary DNA (cDNA) library by Tadatsugu Taniguchi's group.[10] Thus, despite being designated the number 2 interleukin, it was the first interleukin molecule, receptor, and gene to be discovered. It was designated the number 2 interleukin because IL-1, produced by macrophages, facilitates IL-2 production by T lymphocytes (T cells).[11][12] These data served as the scientific rationale for the creation of the interleukin nomenclature, anticipating that more molecules would be discovered. Now, in 2012, there are 37 interleukin molecules.

Signaling pathway

Subsequently, IL-2 was discovered to be a member of a family of cytokines, which also includes IL-4, IL-7, IL-9, IL-15 and IL-21. IL-2 signals through a receptor complex consisting of IL-2 specific IL-2 receptor alpha (CD25), IL-2 receptor beta (CD122) and a common gamma chain (γc), which is shared by all members of this family of cytokine receptor.

Function

IL-2 is necessary for the growth, proliferation, and differentiation of T cells to become 'effector' T cells. IL-2 is normally produced by T cells during an immune response.[13][14] 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[15][16][17] 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).[18][19][20] 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.[21] Both cytokines are able to facilitate production of immunoglobulins made by B cells and induce the differentiation and proliferation of natural killer cells.[22] 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

Disease

IL-2 has been linked to various diseases.

Pruritus (itch)

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.[23]

Immunotherapy

IL-2 has been tested in many clinical trials as an immunotherapy for the treatment of cancers, chronic viral infections and as adjuvants for vaccines.

A recombinant form of human IL-2 for clinical use is manufactured by Prometheus Laboratories, Inc. with the brand name Proleukin. 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, and is 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. However, that does not mean that the drug is ineffective in improving T-cell count. Many persons who underwent IL-2 therapy enjoyed dramatic improvement in T-cell count, as well as overall health. But the FDA determined that the risks and costs (experience of side-effects) outweighed those benefits.

IL-2 and IL-2 receptor blockade as immunosuppression

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.

References

External links

  • Proleukin website
  • IL-2 Signaling Pathway
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