Cytokines receptor family

The class II cytokine receptor family includes receptors for interferon a/P (lEN a/P) and y (lENy) and IL-10. lEN-y immunoreactivity has been found in neurons in the hypothalamus, cerebral cortex, mammilary nuclei, and dorsal tegmentum. Astrocytes and microglia in vitro can be stimulated to express class II histocompatibiHty complex (MHC-II) antigens by lEN-y, which may be involved in the presentation of antigen to T-ceUs by astrocytes. Thus lEN-y may be critical in CNS-immune function and dysfunction especially in regard to neuronal and gHal apoptotic processes. 

The class III cytokine receptor family includes two TNE receptors, the low affinity NGE receptor and 7-ceU surface recognition sites that appear to play a role in proliferation, apoptosis, and immunodeficiency. TNE-a (- 17, 000 protein) is produced by astrocytes and microglia and can induce fever, induce slow-wave sleep, reduce feeding, stimulate prostaglandin synthesis, stimulate corticotrophin-releasing factor and prolactin secretion, and reduce thyroid hormone secretion. TNE-a stimulates IL-1 release, is cytotoxic to oligodendrocytes, and reduces myelination this has been impHcated in multiple sclerosis and encephalomyelitis. Astrocyte TNE-a receptors mediate effects on IL-6 expression and augment astrocytic expression of MHC in response to other stimulants such as lEN-y. 

Studies have actually revealed two type I interferon receptor polypeptides. Sequence data from cloning studies place both in the class II cytokine receptor family. Both are transmembrane N-linked glycoproteins. Studies using isolated forms of each show that one polypeptide (called the a/p receptor) is capable of binding all type I interferons. The other one (the ap receptor) is specific for IFN-a-B (a specific member of the IFN-a family). Both receptors are present on most cell types. 

Moutoussamy, S., Kelly, P.A. and Finidori, J. Growth-hormone-receptor and cytokine-receptor-family signaling (1998) Eur J Biochem 255,1-11... 

Dr. Alain Fisher and his research team have successfully treated two infants with XSCIDS, a severe form of SCIDS that occurs only in boys. These patients lack functional T cells and natural killer cells (NK) due to mutations in the % chain of the cytokine receptor family that recognizes interleukins (i.e., IL-2, -4, -7, -9, and -15). Ex vivo gene transfer was employed. The researchers delivered the wild-type sequence for the yc chain cytokine receptor subunit to hematopoietic stem cells isolated from these patients using a nonreplicating murine retrovirus [14,15]. 

IL-22. IL-10-related T cell-derived inducible factor (IL-TIF provisionally designated IL-22) is a cytokine distantly related to IL-10 and is produced by activated T cells (D16). IL-22 receptor, a new member of the interferon receptor family, and CRF2-4, a member of the class II cytokine receptor family, join together to enable IL-22 signaling. Cell lines that respond to IL-22 by activation of STATs 1,3, and 5, but unresponsive to IL-10, have been identified (XI). In contrast to IL-10, IL-22 does not inhibit the LPS-induced production of proinflammatory cytokines by monocytes, but it has a modest inhibitory effect on IL-4 production from Th2 cells (XI). 

TABLE 22-3 Cytokine Receptor Families and Their Cytokines... 

IL-IOR is a single-chain receptor. IL-IOR belongs to the class II cytokine receptor family that also includes the IFN receptors (IFNy and IFNap receptors). The extracellular region consists of two homologous fibronectin type III domains that are without the WSXWS motif characteristic of class I cytokine receptors. It is expressed on B cells, thymocytes, and other cellular lines such as mast cells and macrophages. Human IL-IOR mRNA is restricted mostly to hematopoietic cells and cell lines. ... 

The high-affinity receptor for IL-11 is composed of two subunits, IL-11 receptor a-chain (IL-llRa) and gpl30, the common subunit of the IL-6, CNTF, LIF, and OSM receptors. The IL-11 receptor-specific a chain shares homologies with the a chain of the CNTF and IL-6 receptors, confirming evolutionary conservation at the level of gene organization among the hematopoietic cytokine receptor family. ... 

IL-17R is unrelated to previously identified cytokine receptor families. A recombinant soluble receptor inhibits T-cell proliferation and IL-2 production induced by mitogens and anti-TCR monoclonal antibodies. It has been suggested that a large variety of cells can express IL-17R, including fibroblasts epithelial and endothelial cells. 

The first specifically binds IFNaB (IFNaS, a variety of IFNa) and is known as the IFNaB receptor. The second bmds both IFNa and IFNp and is called the IFNa/j3 receptor. The IFNapR is a member of the class II cytokine receptor family, which also includes the IFNyR, IL-IOR, and tissue factor. The IFNa/ R is also a class II cytokine receptor and contains at least two components that interact with type I IFNs, It is not known if these two receptors are expressed independently on the cell surface or are associated with each other in an IFN receptor complex. The receptors are present on most types of cells. A soluble form of the IFNa/pR has been identified in human serum and urine. 

Fig. 11.3 Schematic model of the IL-6/gpl 30 receptor system. The specific cytokine-binding subunits and gpl30 belong to a cytokine receptor family characterized by four positionally conserved cysteine and a WSXWS motif. Functional receptor complexes are induced by the different cytokines IL-6 and IL-11 induce gpl30 homodimerization. CNTF, LIF, CT-1 and OSM induce LIFRa/gpl30...

PR, AR, GR, MR), thyroid hormone (TRa and j8), and retinoid (RARot, jS, and 7, and RXRa) receptor superfamily of nuclear transcriptional factors (207-210), multiple members of the interleukin cytokine receptor family (211), and subtypes of the glutamate (212) and adenosine (213)receptor families. The importance of access to human cloned receptors continues to be underscored as receptor binding plays an increasingly critical role in modern drug discovery (214). 

One common feature of the cytokine receptor family, including the IL-6 family, is that its members contain immunoglobulin (Ig)-like domains, of which the structures are similar to that of Ig, in the extracellular site of each subunit (Bazan 1991). Near the C-terminal end of the second domain ( C-terminal domain), there is a cytokine receptor family consensus sequence, W(Trp)-S(Ser)-X(a variable residue)-W-S. 

Murakami, M., Narazaki, M., Hibi, M., Yawata, H., Yasu-kawa, K., Hamaguchi, M., Taga, T. and Kishimoto, T. (1991) Critical cytoplasmic region of the interleukin 6 signal transducer gpl30 is conserved in the cytokine receptor family. Proc. Natl. Acad. Sci. USA 88 11349-11353. 

All effects of GH result from its interactions with the GH receptor, as evidenced by the severe phenotype of rare patients with homozygous mutations of the GH receptor gene (the Laron syndrome of GH-resistant dwarfism). The GH receptor is a widely distributed cell-surface receptor that belongs to the cytokine receptor superfanuly. Like other members of the cytokine receptor family, the GH receptor contains an extracellular domain that binds GH, a single membrane-spanning... 

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