Structure and Function of Cytokine Receptors

A characteristic that significantly differentiates some of the cytokines from other hormones is the coupling of their activity to cell-cell interactions. The function of some cytokines such as the interleukins lL-4, lL-5, lL-6 and lL-10 is closely associated with the interaction between B and T lymphocytes. 

B lymphocytes may be activated by a cell-cell interaction with T lymphocytes, i.e., they are stimulated to proliferate and produce antibodies. Stimulation of B lymphocytes takes place in a complex with T lymphocytes and this complex formation is mediated by a number of protein-protein interactions of membrane proteins from both cell types. The proteins involved are receptor systems with corresponding hgands on the partner cell. Tlie hgands are either secreted proteins or membrane proteins that speci-ficaUy bind to receptors on the surface of the partner cell, which in this case is a B or T lymphocyte. 

At least four types of cytokine receptors can be differentiated on the basis of sequence homology (Fig. 11.2). Many members of the cytokine receptors of type 1 regulate growth and transmit mitogenic signals to the cell nucleus. The cytokine receptors of type 2 include the receptors for the interferons a and p. Type 3 includes the receptors for tiunor necrosis factor TNF and for CD 40 and Fas protein, which are foimd on T lymphocytes. 

In the extracellular region, cytokine receptors have characteristic sequence sections that specify the particular receptor type. Cys-rich domains, fibronectin type Ill-like domains and immimoglobulin-like domains can be differentiated. Cytokine receptors of type I often have a conserved WSXWS motif in the extracellular region. 

The subunit structure of the cytokine receptors is very variable. Amongst the cytokine receptors, there are receptors composed of one polypeptide and receptors made up of two or three different polypeptide chains (Fig. 11.3), which therefore have a hetero-oligomeric structure. The receptors have one transmembrane element per polypeptide chain. The NH2 terminus is located in the extracellular region whilst the CO OH terminus is intracellular. 

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He, Y. W., and Malek, T. R. (1998). The structure and function of gamma c-dependent cytokines and receptors Regulation of T lymphocyte development and homeostasis. Crit. Rev. Immunol. 18, 503-524. 

Genetic engineering allowed production of large quantities of most cytokines. These could be used for structural and functional studies of the cytokine itself, and its receptor. 

The cytokines are of considerable medical importance due to their essential function in controlling the immune system, in defense reactions and for processes of inflammation. Great efforts are therefore being made to elucidate the structure and mechanism of activity of the cytokines and their corresponding receptors and to characterize the components of the signals triggered by cytokines. Many of the cytokines have the cha-... 

Chemoattractant properties are the major biological effect of CKs. Their receptors are G protein-coupled receptors that form a family of structurally and functionally related proteins. CKs are induced in cells and tissue in response to proinflammatory cytokines. They are produced by a large diversity of cells (Figure 22-32). The CK superfamily, with the exception of RANTES, p-TG, HCC-1, and PF-4, is not expressed in resting cells but is rapidly induced in response to various inflammatory and mitogenic stimuli. Probably all CKs have some activities that are unique and many that are... 

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. 

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). 

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