Interleukin 2

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Interleukin 2
IL2 Crystal Structure.png
Human Interleukin 2 crystal structure
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols IL2 ; IL-2; TCGF; lymphokine
External IDs OMIM147680 MGI96548 HomoloGene488 ChEMBL: 5880 GeneCards: IL2 Gene
RNA expression pattern
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:
123.37 – 123.38 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[edit]

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.

Function[edit]

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.[1][2] 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[3][4][5] 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).[6][7][8] 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.[9] Both cytokines are able to facilitate production of immunoglobulins made by B cells and induce the differentiation and proliferation of natural killer cells.[10] 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.[11]

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.

Medical use[edit]

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) for the treatment of cancers (malignant melanoma, renal cell cancer) in large intermittent toxic doses.

Clinical research[edit]

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.[12]

History[edit]

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,[13] 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[14] and Julius Gordon and Lloyd MacLean[15] 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.[16] 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.[17] Smith was also first to show that IL-2 mediates its effects via a specific IL-2 receptor,[18] and it was also the first interleukin molecule to be cloned and expressed from a complementary DNA (cDNA) library by Tadatsugu Taniguchi's group.[19] 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).[20][21] These data served as the scientific rationale for the creation of the interleukin nomenclature, anticipating that more molecules would be discovered.

In popular culture[edit]

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.'"[22]

References[edit]

  1. ^ Cantrell DA, Smith KA (June 1984). "The interleukin-2 T-cell system: a new cell growth model". Science 224 (4655): 1312–6. doi:10.1126/science.6427923. PMID 6427923. 
  2. ^ Smith KA (May 1988). "Interleukin-2: inception, impact, and implications". Science 240 (4856): 1169–76. doi:10.1126/science.3131876. PMID 3131876. 
  3. ^ Stern JB, Smith KA (July 1986). "Interleukin-2 induction of T-cell G1 progression and c-myb expression". Science 233 (4760): 203–6. doi:10.1126/science.3523754. PMID 3523754. 
  4. ^ Beadling C, Johnson KW, Smith KA (April 1993). "Isolation of interleukin 2-induced immediate-early genes". Proc. Natl. Acad. Sci. U.S.A. 90 (7): 2719–23. doi:10.1073/pnas.90.7.2719. PMC 46167. PMID 7681987. 
  5. ^ Beadling C, Smith KA (November 2002). "DNA array analysis of interleukin-2-regulated immediate/early genes". Med Immunol 1 (1): 2. doi:10.1186/1476-9433-1-2. PMC 149405. PMID 12459040. 
  6. ^ Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M (August 1995). "Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases". J. Immunol. 155 (3): 1151–64. PMID 7636184. 
  7. ^ Thornton AM, Shevach EM (July 1998). "CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production". J. Exp. Med. 188 (2): 287–96. doi:10.1084/jem.188.2.287. PMC 2212461. PMID 9670041. 
  8. ^ Thornton AM, Donovan EE, Piccirillo CA, Shevach EM (June 2004). "Cutting edge: IL-2 is critically required for the in vitro activation of CD4+CD25+ T cell suppressor function". J. Immunol. 172 (11): 6519–23. PMID 15153463. 
  9. ^ Waldmann TA (August 2006). "The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design". Nat. Rev. Immunol. 6 (8): 595–601. doi:10.1038/nri1901. PMID 16868550. 
  10. ^ Waldmann TA, Tagaya Y (1999). "The multifaceted regulation of interleukin-15 expression and the role of this cytokine in NK cell differentiation and host response to intracellular pathogens". Annu. Rev. Immunol. 17: 19–49. doi:10.1146/annurev.immunol.17.1.19. PMID 10358752. 
  11. ^ Fallahzadeh MK, Roozbeh J, Geramizadeh B, Namazi MR (October 2011). "Interleukin-2 serum levels are elevated in patients with uremic pruritus: a novel finding with practical implications". Nephrol. Dial. Transplant. 26 (10): 3338–44. doi:10.1093/ndt/gfr053. PMID 21372257. 
  12. ^ NIH staff for NIH News. February 10, 2009 IL-2 Immunotherapy Fails to Benefit HIV-Infected Individuals Already Taking Antiretrovirals
  13. ^ Schrader J. "Interleukins and interleukin receptors". Gene Families. HUGO Gene Nomenclature Committee. Retrieved 2013-12-29. 
  14. ^ Kasakura S, Lowenstein L (November 1965). "A factor stimulating DNA synthesis derived from the medium of leukocyte cultures". Nature 208 (5012): 794–5. doi:10.1038/208794a0. PMID 5868897. 
  15. ^ Gordon J, MacLean LD (November 1965). "A lymphocyte-stimulating factor produced in vitro". Nature 208 (5012): 795–6. Bibcode:1965Natur.208..795G. doi:10.1038/208795a0. PMID 4223737. 
  16. ^ Kasakura S, Taguchi M, Watanabe Y, Okubo T, Murachi T, Uchino H, Hanaoka M (December 1984). "A mitogenic factor, released by stimulated human mononuclear cells and distinct from interleukin 2 (IL 2), B cell growth factor (BCGF), and interleukin 1 (IL 1)". J. Immunol. 133 (6): 3084–90. PMID 6238094. 
  17. ^ Smith KA, Favata MF, Oroszlan S (October 1983). "Production and characterization of monoclonal antibodies to human interleukin 2: strategy and tactics". J Immunol 131 (4): 1808–1815. PMID 6352804. 
  18. ^ Robb RJ, Munck A, Smith KA (November 1981). "T cell growth factor receptors. Quantitation, specificity, and biological relevance". J. Exp. Med. 154 (5): 1455–74. doi:10.1084/jem.154.5.1455. PMC 2186509. PMID 6975347. 
  19. ^ Taniguchi T, Matsui H, Fujita T, Takaoka C, Kashima N, Yoshimoto R, Hamuro J (1983). "Structure and expression of a cloned cDNA for human interleukin-2". Nature 302 (5906): 305–10. Bibcode:1983Natur.302..305T. doi:10.1038/302305a0. PMID 6403867. 
  20. ^ Smith KA, Lachman LB, Oppenheim JJ, Favata MF (June 1980). "The functional relationship of the interleukins". J. Exp. Med. 151 (6): 1551–6. doi:10.1084/jem.151.6.1551. PMC 2185867. PMID 6770028. 
  21. ^ Smith KA, Gilbride KJ, Favata MF (October 1980). "Lymphocyte activating factor promotes T-cell growth factor production by cloned murine lymphoma cells". Nature 287 (5785): 853–5. doi:10.1038/287853a0. PMID 6776414. 
  22. ^ Liz Szabo for USA TODAY. May 18, 2009 Doctors, patients say 'Grey's' cancer story isn't accurate

External links[edit]