Interleukins Proteins


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 Interleukins Proteins Background

Interleukins (ILs) are small proteins which act as mediators of communication between lymphocytes. The interleukins are a subset of lymphokines, a collective term introduced in 1969 to encompass factors which influence blood cells (leukocytes). They are hormones that allow the cells of the immune system to interact indirectly without physical contact. Subtle differences between the classical hormones, such as insulin and interleukins exist. Interleukins act at short range in the local cellular environment. A number of interleukins are produced by a variety of cell types, whereas the classical hormones are usually produced by specific cell types and tissues.
Cloning of cDNAs encoding interleukins in the 1980s was a major step in clarifying the physical nature of soluble factors previously identified in a variety of bioassays. In vitro cloning of T cells, which produce a large quantity of factors, helped to isolate cDNA for such molecules. It was also helpful to have sensitive bioassays for a specific factor, including functional assays for the translated protein product from the cDNA. Molecular biological studies of soluble factors emphasized their role in cell-to-cell communication among leukocytes; hence the term interleukins was introduced. Isolation of cDNAs for interleukins also permitted biochemical studies. The main emphasis was on physical characterization of the specific receptors and studies of signal transduction through ligand-receptor interaction. It has become clear that the interleukins, polypeptide hormones produced by immune cells, have a variety of physiological effects on B cells.
There are several features common to all the interleukins isolated to date. First, they are all secreted polypeptides with heavy glycosylation moiety. The sugar component may account for up to 50 % of the molecular weight of the protein. Second, their functions are pleiotropic; their effects range from growth to differentiation of many types of cells, including lymphocytes. Many ILs share overlapping activities. Thus, the long-held assumption that growth and differentiation are always regulated by different molecular entities has been challenged. The effects of a given interleukin on a given type of cell can be dependent on the developmental stage of the cell receiving the signal. Third, the interleukin molecules act upon cells through binding specific receptors on the target cell surface. Thus, only cells with proper receptors can respond to a specific interleukin. Cloning of interleukin receptors has revealed that they have multiple subunits with distinct functions. Differential combination of such subunits can create receptors with different affinities. Moreover, some interleukin receptors are now known to share a subunit, which might partially explain their functional redundancy.
Three interleukins, IL-2, IL-4, and IL-5, are particularly important for the differentiation of "activated" B cells into IgM secreting cells. These interleukins are produced by T helper cells, and appear to be involved in the growth and differentiation of B cells.
IL-2 was first identified as a T cell mitogenic factor produced by lectin-activated mononuclear cells. It was first named T Cell Growth Factor (TCGF) for its ability to stimulate the growth of normal T cells in vitro. For many years, it was considered to be a T cell specific factor. However, it was realized in the early 1980's that IL-2 also has effects on B cells. Taniguchi et al. successfully isolated the cDNA coding for human Interleukin-2 (IL-2) in 1983 aided by a well established bioassay and a human leukemic T cell line which produces a high amount of IL-2 activity. The mouse cDNA for IL-2 was isolated by cross-hybridization to the human IL-2 cDNA using a cDNA library constructed from a lymphoma cell line.
Molecular cloning of cDNAs coding for IL-4 and IL-5 was facilitated by the establishment of a T cell line (2.19 cell) and sensitive, quantitative, and reproducible assays for BCDF (IgG1 Induction Factor), BSF-1, and BCGF-II. A well characterized murine B-cell factor, T-cell replacing factor (TRF), was previously classified as a BCDF (induction of IgM secretion), but a partially purified preparation of TRF was suggested to have BCGF II activity (stimulation of thymidine incorporation by the in vivo BCL1 leukemic B-cell line.) The identity of TRF with BCGF II was proven by cloning its cDNA and the name IL-5 was proposed for this lymphokine. IL-4 is identical to B-cell stimulating factor-1 (BSF-1), which induces DNA synthesis when given together with anti-IgM antibodies. IL-4 also induces not only an elevated IgG1 response in B cells activated by lipopolysaccharide but also hyper-Ia expression in B cells. Furthermore, this lymphokine reveals growth factor activities for both T and mast cells.
Receptors for IL-2, IL-4 and IL-5 (IL-2R, IL-4R, and IL-5R, respectively) belong to the recently classified Class I cytokine receptor superfamily, whose members have multiple subunits, and some share the same signal transducing subunit. Both IL-2R and IL-4R share a common y subunit along with IL-7R, IL-9R, and IL-15R. IL-5R shares a common  subunit with IL-3 and GM-CSF. Three receptors were originally identified in the human with different affinity for IL-2, with dissociation constants (kd) on the order of 10-11 M, 10-9 M, and 10-8 M, respectively. They are now known to be comprised of three distinct subunits. The high affinity IL-2 receptor is composed of , αβγ,  subunits (IL-2R αβγ) , the intermediate affinity IL-2 receptor with β and  subunits (IL-2R βγ) , and the low affinity IL-2 receptor with a subunit (IL-2R α) in human. In the mouse, there is no intermediate affinity IL-2 receptor complex, but only high affinity IL-2 receptor (IL-2R αβγ) and low affinity IL- 2 receptor (IL-2R α) with dissociation constants (kd) on the order of 10-11 M and 10-8 M, respectively. The three subunits appear to have distinct functions, in the mouse, IL-2 binding appears impossible without the α subunit, and signal transduction without β or γ. IL-4R is a heterodimer consisting of IL-4R α and IL-2R γ. IL-5R is also a hetero-dimer consisting of IL-5R α and IL-5R β.
With the cloning of cDNA for more than fifteen interleukins, it has become clear that overlapping functions of different ILs is a very common phenomenon. The multiplicity of factors, each with subtly different actions, obviously provides the opportunity for a highly regulated response. Their interaction may result in numerous consequences to a cell, and the roles of each interleukin are difficult to assign without having a homogeneous cell population, which will be discussed below. It has already emerged that the roles of B cell-active cytokines are considerably more complex than first envisaged. 
One of the most important findings in the pursuit of T helper cell characterization was the discovery heterogeneity in T helper cells, identified as cell surface phenotype of CD4+ and CD8-. In late 1980s, murine T helper (Th) cells were shown to be divided into two subsets: Th-1 and Th-2. This definition is based on the specific interleukins they produce. Th-1 cells produce IL-2, IFN, and TNF-β; and Th-2 cells produce IL-4, IL-5, IL-6, and IL-10. The difference in the cytokine profile is thought to reflect biological functions of these two subsets of CD4+ Th cells: Th-1 for the classical cell mediated response and Th-2 for more efficient helper function in the humoral response i.e., B cell activation. Several diseases appear to be related to cytokine expression, such as over expression of IL-1 and IFN with bacterial septic shock.