Interleukin

Interleukins are a group of cytokines (secreted proteins/signaling molecules) that were first seen to be expressed by white blood cells (leukocytes). The term interleukin derives from (inter-) "as a means of communication", and (-leukin) "deriving from the fact that many of these proteins are produced by leukocytes and act on leukocytes". The name is something of a relic though (the term was coined by Dr. Paetkau, University of Victoria); it has since been found that interleukins are produced by a wide variety of body cells. The function of the immune system depends in a large part on interleukins, and rare deficiencies of a number of them have been described, all featuring autoimmune diseases or immune deficiency. The majority of interleukins are synthesized by helper CD4+ T lymphocytes, as well as through monocytes, macrophages, and endothelial cells. They promote the development and differentiation of T, B, and hematopoietic cells.

Interleukin receptors on astrocytes in the hippocampus are also known to be involved in the development of spacial memories in mice.

Interleukin-1
Interleukin-1 alpha and interleukin-1 beta (IL-1 alpha and IL-1 beta) are cytokines that participate in the regulation of immune responses, inflammatory reactions, and hematopoiesis. Two types of IL-1 receptor, each with three extracellular immunoglobulin (Ig)-like domains, limited sequence similarity (28%) and different pharmacological characteristics have been cloned from mouse and human cell lines: these have been termed type I and type II receptors. The receptors both exist in transmembrane (TM) and soluble forms: the soluble IL-1 receptor is thought to be post-translationally derived from cleavage of the extracellular portion of the membrane receptors.

Both IL-1 receptors (CD121a/IL1R1, CD121b/IL1R2) appear to be well conserved in evolution, and map to the same chromosomal location. The receptors can both bind all three forms of IL-1 (IL-1 alpha, IL-1 beta and IL-1RA).

The crystal structures of IL1A and IL1B have been solved, showing them to share the same 12-stranded beta-sheet structure as both the heparin binding growth factors and the Kunitz-type soybean trypsin inhibitors. The beta-sheets are arranged in 3 similar lobes around a central axis, 6 strands forming an anti-parallel beta-barrel. Several regions, especially the loop between strands 4 and 5, have been implicated in receptor binding.

Molecular cloning of the Interleukin 1 Beta converting enzyme is generated by the proteolytic cleavage of an inactive precursor molecule. A complementary DNA encoding a protease that carries out this cleavage has been cloned. Recombinant expression enabled cells to process precursor Interleukin 1 Beta to the mature form of the enzyme.

Interleukin-1 also plays a role in the central nervous system. Research indicates that mice with a genetic deletion of the IL-1 receptor type I display markedly impaired hippocampal-dependent memory functioning and Long-term potentiation, although memories that do not depend on the integrity of the hippocampus seem to be spared. However when mice with this genetic deletion have wild-type neural precursor cells injected into their hippocampus and these cells are allowed to mature into astrocytes containing the interleukin-1 receptor, the mice exhibit normal hippocampal-dependant memory function, and partial restoration of Long-term potentiation.

Interleukin-2
T-Lymphocytes regulate the growth and differentiation of certain lymphopoietic and haemopoietic cells through the release of various secreted protein factors. These factors, which include interleukin-2 (IL2), are secreted by lectin- or antigen-stimulated T-cells, and have various physiological effects. IL2 is a lymphokine that induces the proliferation of responsive T-cells. In addition, it acts on some B-cells, via receptor-specific binding, as a growth factor and antibody production stimulant. The protein is secreted as a single glycosylated polypeptide, and cleavage of a signal sequence is required for its activity. Solution NMR suggests that the structure of IL2 comprises a bundle of 4 helices (termed A-D), flanked by 2 shorter helices and several poorly-defined loops. Residues in helix A, and in the loop region between helices A and B, are important for receptor binding. Secondary structure analysis has suggested similarity to IL4 and granulocyte-macrophage colony stimulating factor (GMCSF).

Interleukin-3
Interleukin-3 (IL3) is a cytokine that regulates blood-cell production by controlling the production, differentiation and function of granulocytes and macrophages. The protein, which exists in vivo as a monomer, is produced in activated T-cells and mast cells, and is activated by the cleavage of an N-terminal signal sequence.

IL3 is produced by T-lymphocytes and T-lymphomas only after stimulation with antigens, mitogens, or chemical activators such as phorbol esters. However, IL3 is constitutively expressed in the myelomonocytic leukaemia cell line WEHI-3B. It is thought that the genetic change of the cell line to constitutive production of IL3 is the key event in development of this leukaemia.

Interleukin-5
Interleukin-5 (IL5), also known as eosinophil differentiation factor (EDF), is a lineage-specific cytokine for eosinophilpoiesis. It regulates eosinophil growth and activation, and thus plays an important role in diseases associated with increased levels of eosinophils, including asthma. IL5 has a similar overall fold to other cytokines (e.g., IL2, IL4 and GCSF), but while these exist as monomeric structures, IL5 is a homodimer. The fold contains an anti-parallel 4-alpha-helix bundle with a left handed twist, connected by a 2-stranded anti-parallel beta-sheet. The monomers are held together by 2 interchain disulphide bonds.

Interleukin-6
Interleukin-6 (IL6), also referred to as B-cell stimulatory factor-2 (BSF-2) and interferon beta-2, is a cytokine involved in a wide variety of biological functions. It plays an essential role in the final differentiation of B-cells into IG-secreting cells, as well as inducing myeloma/plasmacytoma growth, nerve cell differentiation, and, in hepatocytes, acute-phase reactants.

A number of other cytokines may be grouped with IL6 on the basis of sequence similarity. These include granulocyte colony-stimulating factor (GCSF) and myelomonocytic growth factor (MGF). GCSF acts in hematopoiesis by affecting the production, differentiation, and function of 2 related white cell groups in the blood. MGF also acts in hematopoiesis, stimulating proliferation and colony formation of normal and transformed avian cells of the myeloid lineage.

Cytokines of the IL6/GCSF/MGF family are glycoproteins of about 170 to 180 amino acid residues that contains four conserved cysteine residues involved in two disulphide bonds:. They have a compact, globular fold (similar to other interleukins), stabilised by the 2 disulphide bonds. One half of the structure is dominated by a 4-alpha-helix bundle with a left-handed twist; the helices are anti-parallel, with 2 overhand connections, which fall into a 2-stranded anti-parallel beta-sheet. The fourth alpha-helix is important to the biological activity of the molecule.

Interleukins 7 and 9
Interleukin-7 (IL-7) is a cytokine that serves as a growth factor for early lymphoid cells of both B- and T-cell lineages. Interleukin-9 (IL-9) is a cytokine that supports IL-2 independent and IL-4 independent growth of helper T-cells. Interleukin-7 and -9 seems to be evolutionary related.

Interleukin-10
Interleukin-10 (IL-10) is a protein that inhibits the synthesis of a number of cytokines, including IFN-gamma, IL-2, IL-3, TNF, and GM-CSF produced by activated macrophages and by helper T cells. In structure, IL-10 is a protein of about 160 amino acids that contains four conserved cysteines involved in disulphide bonds. IL-10 is highly similar to the Human herpesvirus 4 (Epstein-Barr virus) BCRF1 protein, which inhibits the synthesis of gamma-interferon and to Equid herpesvirus 2 (Equine herpesvirus 2) protein E7. It is also similar, but to a lesser degree, with human protein mda-7. a protein that has antiproliferative properties in human melanoma cells. Mda-7 contains only two of the four cysteines of IL-10.

Interleukin-11
Interleukin-11 (IL-11) is a secreted protein that stimulates megakaryocytopoiesis, resulting in increased production of platelets, as well as activating osteoclasts, inhibiting epithelial cell proliferation and apoptosis, and inhibiting macrophage mediator production. These functions may be particularly important in mediating the hematopoietic, osseous and mucosal protective effects of interleukin 11. Family members seem to be restricted to mammals.

Interleukin 12
Interleukin-12 (IL-12) is a disulphide-bonded heterodimer consisting of a 35kDa alpha subunit and a 40kDa beta subunit. It is involved in the stimulation and maintenance of Th1 cellular immune responses, including the normal host defence against various intracellular pathogens, such as Leishmania, Toxoplasma, Measles virus, and Human immunodeficiency virus 1 (HIV). IL-12 also has an important role in pathological Th1 responses, such as in inflammatory bowel disease and multiple sclerosis. Suppression of IL-12 activity in such diseases may have therapeutic benefit. On the other hand, administration of recombinant IL-12 may have therapeutic benefit in conditions associated with pathological Th2 responses.

Interleukin-13
Interleukin-13 (IL-13) is a pleiotropic cytokine that may be important in the regulation of the inflammatory and immune responses. It inhibits inflammatory cytokine production and synergises with IL-2 in regulating interferon-gamma synthesis. The sequences of IL-4 and IL-13 are distantly related.

Interleukin-15
Interleukin-15 (IL-15) is a cytokine that possesses a variety of biological functions, including stimulation and maintenance of cellular immune responses. IL-15 stimulates the proliferation of T-lymphocytes, which requires interaction of IL-15 with components of IL-2R, including IL-2R beta and probably IL-2R gamma, but not IL-2R alpha.

Interleukin-17
Interleukin-17 (IL-17) is a potent proinflammatory cytokine produced by activated memory T cells. The IL-17 family is thought to represent a distinct signalling system that appears to have been highly conserved across vertebrate evolution.

List of human interleukins
A list of interleukins: