Cytokine Receptor Function

Cytokine receptors are a group of structurally related receptors, which couple to the JAK-STAT pathway. Cytokine receptors function as homodimers or heterooligomers. They are divided into two main subclasses, class I, which contains receptors for a variety of hematopoietic growth factors and interleukins and class II, which contains receptors for interferons and interleukins 10, 20/24 and 22. 

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 theoretical complications posed by random chromosomal integration became a medical reality in 2002, when two children who had received retroviral-based gene therapy 2 years previously developed a leukaemic-like condition. The initial clinical trial aimed to treat X-linked severe combined immunodeficiency (SCID-X1), a hereditary disorder in which T-lymphocytes and NK cells in particular do not develop, due to a mutation in the gene coding for the yc cytokine receptor subunit. The clinical consequence is near abolition of a functional immune system. 

IL-13 on keratinocytes, two Th-2 cytokines which function via the same receptor in this cell type [26]. IL-13 or IL-4-stimulated keratinocytes attract CCR4+CD4-I- Th-2 cells via CCL22 [27]. Moreover, IL-13 induces the expression of MMP-9 in keratinocytes [28] which may play a crucial role in atopic skin inflammation by facilitating the migration of leukocytes into the epidermis. 

In addition to receptor tyrosine kinases, the cell also contains a number of tyrosine-specific protein kinases that are not an integral component of transmembrane receptors. These nonreceptor tyrosine kinases are localized in the cytoplasm at least occasionally or they are associated with transmembrane receptors on the cytoplasmic side of the cell membrane. They are therefore also known as cytoplasmic tyrosine kinases. The nonreceptor tyrosine kinases perform essential functions in signal transduction via cytokine receptors (see Chapter 11) and T cell receptors, and in other signaling pathways. 

Cytokines are proteins that serve as signal molecules in cell-cell communication, and as such, perform a central and very diverse function in growth and differentiation of an organism. Representatives of cytokines control proliferation, differentiation and function of cells of the immune system and of cells of the blood-forming system. Furthermore, they are involved in processes of inflammation and in the neuronal, hema-poetic and embryonal development of the organism. Known cytokines include the interleukins (IL), erythropoietin, growth hormone, interferons (INF) and tumor necrosis factor (TNF) (see Table 8.1). A review of cytokines and cytokine receptors is to be found in HiU and Treisman, (1995) Taniguchi et al., (1995) and Moutoussamy et al., (1998). 

Fig. 11.6. Model of activation of Jak kinases. The Jak kinases (Jakl and Jak2 are shown as examples here) are attributed a two-fold function in signal transduction via cytokine receptors. On binding to the activated cytokine receptor, the Jak kinases are activated and phosphorylation of the Jak kinases takes place, probably by a trans mechanism (dashed arrow). The Jak kinases also catalyze Tyr phosphorylation of the cytoplasmic domain of the receptor (solid arrow). The phosphotyrosine residues serve as attachment points for adaptor proteins or other effector proteins.

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]. 

Pace TW, Hu F, Miller AH Cytokine-effects on glucocorticoid receptor function Relevance to glucocorticoid resistance and the pathophysiology and treatment of major depression. Brain Behav Immun 2007 21(1) 9. [PMID 17070667]... 

Erythropoietin stimulates erythroid proliferation and differentiation by interacting with erythropoietin receptors on red cell progenitors. The erythropoietin receptor is a member of the JAK/STAT superfamily of cytokine receptors that use protein phosphorylation and transcription factor activation to regulate cellular function (see Chapter 2). Erythropoietin also induces release of reticulocytes from the bone marrow. Endogenous erythropoietin is primarily produced in the kidney. In response to tissue hypoxia, more erythropoietin is produced through an increased rate of transcription of the... 

Cytokines all function using a group of transmembrane receptors embedded in the plasma membranes of target cells. The receptors have no tyrosine kinase activity but associate with and activate kinases known as Janus kinases (JAKs). These kinases phosphory-late tyrosine side chains in their receptors, and the phosphorylated receptors activate transcription factors of the STAT (signal transducer-activators of transcription) group.186-195 The specificity of cytokine action results from a combination of receptor recognition and recognition of the various STAT molecules by different JAKs.111 Cytokines have a variety of structures. Many are helix bundles or have (3 sheet structures (Fig. 30-6). 

Aasland, D., Schuster, B., Grotzinger, J., Rosejohn, S., and Kallen, K. J. (2003). Analysis of the leukemia inhibitory factor receptor functional domains by chimeric receptors and cytokines. Biochemistry 42, 5244-5252. 

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