- Interleukin 2
Interleukin-2 (IL-2) is an
interleukin, a type of cytokine immune systemsignaling molecule, that is instrumental in the body's natural response to microbial infectionand in discriminating between foreign (non-self) and self. IL-2 mediates its effects by binding to IL-2 receptors, which are expressed by lymphocytes, the cells that are responsible for immunity.
Discovery and characterization
IL-2 was the first interleukin molecule to be discovered. The discovery of the first soluble "hormone-like" mediator of the immune system galvanized the field of immunology as the important role of cytokines had not been previously demonstrated or appreciated. A soluble "activity" mitogenic for lymphocytes was first found in 1965 in the culture media of mixed leukocytes.. [cite journal | author=Kasakura S, Lowenstein L| title=| A factor stimulating DNA synthesis derived from the medium of leukocyte cultures | date=1965 | journal=Nature | volume=208 | pages=794–795 | ] [cite journal | author=Gordon J, Maclean LD| title=A Lymphocyte-stimulating Factor produced in vitro | date=1965 | journal=Nature | volume=208 | pages=795–796 | doi=10.1038/208795a0] Subsequently, more than 10 years later T cell growth factor (TCGF) was first characterized as a soluble activity in lymphocyte conditioned media that supported the long-term proliferation of T cells in culture. [cite journal | author=Gillis S, Ferm M, Ou W, Smith KA| title=T cell growth factor: Parameters of production and a quantitative microassay for activity| date=1978 | journal=J. Immunol. | volume=120 | pages=2027-2032 | ] Subsequent biochemical characterization of TCGF activity revealed it to be due to a variably
glycosylated15,500 Dalton single protein molecule, [cite journal | author=Robb R, Smith KA | title=Heterogeneity of human T-cell growth factor(s) due to variable glycosylation | date=1981 | journal=Mol. Immunol. | volume=18 | pages=1087–94 | pmid=6977702 | doi=10.1016/0161-5890(81)90024-9] and the IL-2 molecule was first purified to homogeneity by immunoaffinity chromatography. [cite journal | author=Smith KA, Favata MF, Oroszlan S | title=Production and characterization of monoclonal antibodies to human interleukin 2: strategy and tactics | date=1983 | journal=J. Immunol. | volume=131 | pages=1808 | pmid=6352804] IL-2 was also the first cytokine shown to mediate its effects via a specific IL-2 receptor. [cite journal | author=Robb RJ, Munck A, Smith KA | title=T cell growth factor receptors. Quantitation, specificity, and biological relevance | date=1981 |journal=J. Exp. Med. |volume=154| issue=5| pages=1455–74 | pmid= 6975347 | doi=10.1084/jem.154.5.1455] , and it was also the first interleukin to be cloned and expressed from a complementary DNA (cDNA) library, [cite journal | author=Taniguchi T, Matsui H, Fujita T, Takaoka C, Kashima N, Yoshimoto R, Hamuro J | title=Structure and expression of a cloned cDNA for human interleukin-2 | date=1983 | journal=Nature. | volume=302 | issue=5906 | pages=305 | pmid=6403867 | doi=10.1038/302305a0] . Thus, despite being designated the number 2 interleukin, it was the first interleukin molecule, receptor and gene to be discovered. It was designated number 2 because data at the time indicated that IL-1, produced by macrophages, facilitates IL-2 production by T lymphocytes (T cells). [cite journal | author=Smith KA, Lachman LB, Oppenheim JJ, Favata MF | date=1980 | title=The functional relationship of the interleukins | journal=J. Exp. Med. | issue=6 | volume= 151 | pages=1551–6 | pmid=6770028 | doi=10.1084/jem.151.6.1551] [ cite journal | author=Smith KA, Gilbride KJ, Favata MF | title=Lymphocyte activating factor promotes T-cell growth factor production by cloned murine lymphoma cells | date=1980 | journal=Nature. | volume=287 | issue=5785 | pages=853–5 | pmid=6776414 | doi=10.1038/287853a0]
IL-2 signaling pathway
Interleukin-2 belongs to a family of cytokines, which includes
IL-4, IL-7, IL-9, IL-15and 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 cytokines. Binding of IL-2 activates the Ras/MAPK, JAK/Stat and PI 3-kinase/Akt signaling modules. More comprehensive details are provided in [http://www.netpath.org/pathways?path_id=NetPath_14 NetPath] .
Physiology and immunology
IL-2 is normally produced by the body during an immune response. [cite journal | author=Cantrell DA, Smith KA | title=The interleukin-2 T-cell system: a new cell growth model | date=1984 | journal= Science. | volume=224 | pages=1312–6 | pmid=6427923 | doi=10.1126/science.6427923] [cite journal | author=Smith KA | title=Interleukin-2: inception, impact, and implications | date=1988 | journal=Science. | volume=240 | pages=1169–76 | pmid=3131876 | doi=10.1126/science.3131876] When environmental substances (molecules or microbes) gain access to the body, these substances (termed
antigens) are recognized as foreign by antigen receptors that are expressed on the surface of lymphocytes. 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-selected cytotoxic T cellsvia the activation of the expression of specific genes. [cite journal | author=Stern J, Smith KA | title=Interleukin-2 induction of T-cell G1 progression and c-myb expression | date=1986 | journal=Science. |volume=233 | pages=203–6 | pmid=3523754 | doi=10.1126/science.3523754] [cite journal | author=Beadling C, Johnson KW, Smith KA| date=1993 | title=Isolation of interleukin 2-induced immediate-early genes | journal=Proc. Nat. Acad. Sci. U.S.A. | volume=90 | pages=2719–23 | pmid=7681987 | doi=10.1073/pnas.90.7.2719 ] [}cite journal | author=Beadling CB, Smith KA | date=2002 | title=DNA array analysis of interleukin-2-regulated immediate/early genes | journal=Med. Immunol. | volume=1 | pages=2 | pmid=12459040 | doi=10.1186/1476-9433-1-2] As such, IL-2 is necessary for the development of T cell immunologic memory, one of the unique characteristics of the immune system, 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 unique subset of T cells that are termed
regulatory T cells(T-regs). [cite journal | author=Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M | title=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 | date=1995 | journal=J. Immunol. | volume=155 | pages=1151–64 | pmid=7636184 ] cite journal | author=Thornton AM, Shevach EM | title=CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production | date=1998 | journal=J. Exp. Med. | volume=188 | pages=287–96 | pmid=9670041 | doi=10.1084/jem.188.2.287] [cite journal | author=Thornton AM, Donovan EE, Piccirillo CA, Shevach EM | title=Cutting edge: IL-2 is critically required for the in vitro activation of CD4+CD25+ T cell suppressor function | date=2004 | journal=J. Immunol. | volume=172 | pages=6519–23 | pmid=15153463 ] 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 Thus, IL-2 is required to discriminate between self and non-self, another one of the unique characteristics of the immune system.
IL-2 has been found to be similar to IL-15 in terms of function.cite journal | author=Waldmann TA | title=The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design | date=2006 | journal=Nature Rev. Immun. | volume=6 | issue=8 | pages=595–601 | pmid=16868550 | doi=10.1038/nri1901 ] Both cytokines are able to facilitate production of
immunoglobulinsmade by B cellsand induce the differentiation and proliferation of natural killer cells. [cite journal | author=Waldmann TA, Tagaya Y | title=The multifaceted regulation of interleukin-15 expression and the role of this cytokine in NK cell differentiation and host response to intracellular pathogens | date=1999 | journal=Annu. Rev. Immunol.|volume=17 | pages=19–49 | pmid=10358752 | doi=10.1146/annurev.immunol.17.1.19] The primary differences between IL-2 and IL-15 are found in adaptive immune responses. For example, IL-2 participates in maintenance of T-Regs and reduces self-reactive T cells. On the other hand, IL-15 is necessary for maintaining highly specific T cellresponses by supporting survival of CD8 memory T cells. The differences in function in these two cytokines stem from the signal transductionmechanisms and differing receptors.
Uses in medicine
The World Reference Standard for IL-2 is produced by the National Institute of Biological Standards and Control in the UK. A recombinant form of IL-2 for clinical use is manufactured by
Chiron Corporationwith 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), and is in clinical trials for the treatment of chronic viral infections, and as a booster (adjuvant) for vaccines. The role of IL-2 in HIV therapy remains to be fully determined.
Many of the immunosuppressive drugs used in the treatment of autoimmune diseases such as
corticosteroids, and organ transplant rejection ( cyclosporine, tacrolimus) work by inhibiting the production of IL-2 by antigen-activated T cells. Others ( Rapamycin) block IL-2R signaling, thereby preventing the clonal expansion and function of antigen-selected T cells.
* [http://www.proleukin.com Proleukin website]
* [http://www.kendallasmith.us IL2 Resource Site]
* [http://www.netpath.org/pathways?path_id=NetPath_14 IL-2 Signaling Pathway]
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