Interleukin 2
Encyclopedia
Interleukin-2 is an interleukin
, a type of cytokine
immune system
signaling molecule, which is a leukocytotrophic hormone that is instrumental in 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, the cells that are responsible for immunity.
single protein molecule, and the IL-2 molecule was first purified to homogeneity by immunoaffinity chromatography by Kendall Smith and his team at Dartmouth Medical School. IL-2 was also the first cytokine shown to mediate its effects via a specific IL-2 receptor, and it was also the first interleukin to be cloned and expressed from a complementary DNA (cDNA) library. 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 Smith's data at the time indicated that IL-1, produced by macrophages, facilitates IL-2 production by T lymphocytes (T cells).
, 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 cytokines. Binding of IL-2 activates the Ras/MAPK, JAK/Stat and PI 3-kinase/Akt signaling modules. More comprehensive details are provided in NetPath.
) 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 cells via the activation of the expression of specific genes. 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). 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. 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 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 cell
responses by supporting survival of CD8
memory T cells
.
for the treatment of cancers, chronic viral infections and as adjuvants for vaccines.
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 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), and is in clinical trials for the treatment of chronic viral infections, and as a booster (adjuvant) for vaccines. The use of IL-2 in HIV therapy has been found to be ineffective by the FDA. 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.
s, and organ transplant rejection (ciclosporin
, 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.
Interleukin
Interleukins are a group of cytokines that were first seen to be expressed by white blood cells . The term interleukin derives from "as a means of communication", and "deriving from the fact that many of these proteins are produced by leukocytes and act on leukocytes"...
, a type of cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
signaling molecule, which is a leukocytotrophic hormone that is instrumental in the body's natural response to microbial infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
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, 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 realized. A soluble factor mitogenic for lymphocytes was first found in 1965 in the culture media of mixed leukocytes and named Blastogenic Factor (BF). Over the next decade many similar reports appeared that described mitogenic activities in lymphocyte conditioned media. A quantitative assay for T cell Growth Factor (TCGF) was developed based upon its activity to promote the long-term proliferation of T cells in culture. Biochemical characterization of TCGF revealed it to be due to a variably glycosylated 15,500 daltonAtomic mass unit
The unified atomic mass unit or dalton is a unit that is used for indicating mass on an atomic or molecular scale. It is defined as one twelfth of the rest mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state, and has a value of...
single protein molecule, and the IL-2 molecule was first purified to homogeneity by immunoaffinity chromatography by Kendall Smith and his team at Dartmouth Medical School. IL-2 was also the first cytokine shown to mediate its effects via a specific IL-2 receptor, and it was also the first interleukin to be cloned and expressed from a complementary DNA (cDNA) library. 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 Smith's data at the time indicated that IL-1, produced by macrophages, facilitates IL-2 production by T lymphocytes (T cells).
IL-2 signaling pathway
Subsequently, IL-2 was discovered to be a member of a family of cytokines, which also includes IL-4, IL-7Interleukin 7
IL-7 a hematopoietic growth factor secreted by stromal cells in the red marrow and thymus. It is also produced by keratinocytes, dendritic cells, hepatocytes, neurons, and epithelial cells but is not produced by lymphocytes.- Genetics :...
, IL-9
Interleukin 9
Interleukin 9, also known as IL9, is a cytokine belonging to the group of interleukins.-Further reading:...
, IL-15
Interleukin 15
Interleukin 15 is a cytokine with structural similarity to IL-2. Like IL-2, IL-15 binds to and signals through the IL-2/IL-15 beta chain and the common gamma chain . IL-15 is secreted by mononuclear phagocytes following infection by virus...
and IL-21
Interleukin 21
Interleukin-21 is a protein that in humans is encoded by the IL21 gene.Interleukin 21 is a cytokine that has potent regulatory effects on cells of the immune system, including natural killer cells and cytotoxic T cells that can destroy virally infected or cancerous cells...
. IL-2 signals through a receptor complex consisting of IL-2 specific IL-2 receptor alpha (CD25
CD25
CD25 is the alpha chain of the IL-2 receptor. It is a type I transmembrane protein present on activated T cells, activated B cells, some thymocytes, myeloid precursors, and oligodendrocytes that associates with CD122 to form a heterodimer that can act as a high-affinity receptor for IL-2.CD25 is...
), IL-2 receptor beta (CD122) and a common gamma chain
Common gamma chain
The common gamma chain , also known as interleukin-2 receptor subunit gamma or IL-2RG, is a cytokine receptor sub-unit that is common to the receptor complexes for at least six different interleukin receptors: IL-2, IL-4, IL-7, IL-9, IL-15 and interleukin-21 receptor...
(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 NetPath.
Immunological Function
IL-2 is normally produced by the body during an immune response. 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 (TCRT cell receptor
The T cell receptor or TCR is a molecule found on the surface of T lymphocytes that is responsible for recognizing antigens bound to major histocompatibility complex molecules...
) 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 cells via the activation of the expression of specific genes. 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). 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. 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
Adaptive immune system
The adaptive immune system is composed of highly specialized, systemic cells and processes that eliminate or prevent pathogenic growth. Thought to have arisen in the first jawed vertebrates, the adaptive or "specific" immune system is activated by the “non-specific” and evolutionarily older innate...
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 cell
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
responses by supporting survival of CD8
CD8
CD8 is a transmembrane glycoprotein that serves as a co-receptor for the T cell receptor . Like the TCR, CD8 binds to a major histocompatibility complex molecule, but is specific for the class I MHC protein. There are two isoforms of the protein, alpha and beta, each encoded by a different gene...
memory T cells
Memory T cells
Memory T cells are a subset of infection- as well as potentially cancer-fighting T cells that have previously encountered and responded to their cognate antigen; thus, the term antigen-experienced T cell is often applied. Such T cells can recognize foreign invaders, such as bacteria or viruses,...
.
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.Immunotherapy
IL-2 has been tested in many clinical trials as an immunotherapyImmunotherapy
Immunotherapy is a medical term defined as the "treatment of disease by inducing, enhancing, or suppressing an immune response". Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies. While immunotherapies that reduce or suppress are...
for the treatment of cancers, chronic viral infections and as adjuvants for vaccines.
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 Prometheus Laboratories Inc with the brand name Proleukin. It has been approved by the Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(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 use of IL-2 in HIV therapy has been found to be ineffective by the FDA. 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.
Blocking IL-2 receptor
Many of the immunosuppressive drugs used in the treatment of autoimmune diseases such as corticosteroidCorticosteroid
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex. Corticosteroids are involved in a wide range of physiologic systems such as stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte...
s, and organ transplant rejection (ciclosporin
Ciclosporin
Ciclosporin , cyclosporine , cyclosporin , or cyclosporin A is an immunosuppressant drug widely used in post-allogeneic organ transplant to reduce the activity of the immune system, and therefore the risk of organ rejection...
, tacrolimus
Tacrolimus
Tacrolimus is an immunosuppressive drug that is mainly used after allogeneic organ transplant to reduce the activity of the patient's immune system and so lower the risk of organ rejection...
) work by inhibiting the production of IL-2 by antigen-activated T cells. Others (sirolimus
Sirolimus
Sirolimus , also known as rapamycin, is an immunosuppressant drug used to prevent rejection in organ transplantation; it is especially useful in kidney transplants. A macrolide, sirolimus was first discovered as a product of the bacterium Streptomyces hygroscopicus in a soil sample from Easter...
) block IL-2R signaling, thereby preventing the clonal expansion and function of antigen-selected T cells.