Family of Cytokines and Receptors

The three-dimensional structures are known for many gplSO cytokines including murine LIF (Robinson et al, 1994), human LIF (Hinds et al, 1998), CNTF (McDonald et al, 1995), human Interleukin 6 (IL-6) (Somers et al, 1997), HHV-8 IL-6 (Chow et al, 2001a) and oncostatin M (OSM) 

In a similar fashion to the classical GH system, gplSO cytokines mediate the assembly of higher-order signaling complexes through distinct epitopes. The sites I and II, originally identified in GH, formed by distinct helical faces of the four-helix bundle are conserved in the gplSO cytokines. In addition, gplSO cytokines also include a third epitope, termed site III, 

A New Cytokine Receptor Recognition Module The Logic of Site III 

The growth hormone structure established the architecture of the site I and II interactions in a homodimeric receptor complex. The viral and human IL-6 complexes with gplSO extend this paradigm to heterodimeric complexes but also elaborate the modular epitope concept by adding the site III. It is clear from the gplSO complexes that in the case of the HHV-8 IL-6, a site II is used for the gplSO GHR contact. In the human structure, a site I is used for the a. receptor and a site II is used for the gplSO GHR interaction. Similar to GH, in the human IL-6 structure, precomplexation 

A Structural Basis of gp130 Cross-Reactivity Site II 

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Fig. 3. The gplSO family of cytokines and receptors. Schematic representation of gpl30 and leukemia inhibitory factor receptor (LIFR) oriented in a cell membrane. Of the four-helix bundle gplSO cytokines, structural information currently exists for human interleukin 6 (IL-6) (green) (Somers et al, 1997), human herpes virus interleukin 6 (HlTV-8 IL-6) (purple) (Chow et al, 2001a), ciliary neurotrophic factor (CNTF) (orange) (McDonald et al., 1995), leukemia inhibitory factor (LIF) (blue) (Robinson et al, 1994), and oncostatin-M (OSM) (red) (Deller et al, 2000). Lower panel is a detailed list of gplSO cytokines and the associated receptors incorporated into the final signaling complex. (See Color Insert.)...

The interleukin family of cytokines has been overviewed in Chapter 9, and a number of cytokines are known to influence haemopoiesis. The IL-3 receptor, for example, is found on a wide variety of progenitor haemopoietic cells, and appears to stimulate not only CFU-GEMM, but also the precursor cells of basophils, eosinophils and platelets. The role of IL-11, which also plays a role, was also discussed in Chapter 9. 

Many cytokines exhibit redundancy, i.e. two or more cytokines can induce a similar biological effect. Examples include TNF-a and -P, both of which bind to the same receptor and induce very similar if not identical biological responses. This is also true of the interferon-a family of proteins and interferon-/ , all of which bind the same receptor. 

Fig. 3.1 Families of cytokine receptors the cytokine receptors are classified into five major families immunoglobulin superfamily receptors, type I cytokine receptors, type II cytokine receptors, TNF-like receptors and chemokine receptors. The drawings illustrate their general biochemical structure (see Color Insert)...

All of the above families are imperative for homeostatic functions as well as the orchestration of response to pathogenic insult by the immune system. As investigations carry on, this large family wall likely see the emergence of additional cytokines and grow th factors, and the family and sub-families of cytokine, grow th factor, or chemokine receptors wall continue to evolve and expand. 

Molecules having this structure constitute the largest family of cytokines. These molecules have an antiparallel four-a-helical bundle structure (A, B, C, and D helices, A-D and B-C helix pairs). The A-D helix pair frequently represents the region that interacts with the appropriate receptors. 

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... 

IL-18 is a member of the IL-1 family of cytokines. It is present as an inactive precursor in most cell types and is activated by cas-pase-1 activity [71]. IL-18 binds to IL-18 receptors initiating a signal transduction cascade ultimately activating NFkB, which is responsible for its pro-inflammatory effects [71]. IL-18 has been shown to be elevated in urine of patients with acute tubular necrosis [72] and has also been shown to predict mortality in intensive care patients [73]. In addition, urinary IL-18 has been shown to predict dialysis and graft recovery after kidney transplantation [74] and contrast-induced nephropathy [75]. IL-18 is also expressed in cells in vitro, and IL-18 expression has been shown to be induced by TGF-beta in cultured human proximal tubule cells [76],... 

Inflammation is induced by the release of proinflammatory mediators from the cytosol of damaged or infected cells (Sect. 13.2.2). One of the first identified cytokines was an osteoclast activation factor later found to induce a multitude of other proinflammatory events, InterLeukin-1 (IL-1). A second was Tumor Necrosis Factor (TNF), more formally known as tumor necrosis factor-alpha, TNF-a (Sect. 13.2.2). The binding of these proteins to receptors on adjacent cells activates Nuclear Factor kappa B (NFkB), a protein in the leukocyte cytosol. The hgand-bound receptor indirectly phosphorylates an NFkB partner protein (Inhibitor of NFkB, IkB) in the cytosol. The phosphorylated IkB is targeted for destruction and its loss exposes a nuclear locahzation sequence on the NFkB protein which can now enter the nucleus where it induces the expression of important proteins, depending on the type of cell that is activated. ODAR is a Receptor Activator of Nuclear Factor kappa B (RANK), one of a large family of proinflammatory hgand receptors on leukocytes. 

Apoptosis can be induced in mammalian cells by a number of mechanisms, but only two pathways, both for activating caspases, have been elucidated in detail [13]. The death receptor or extrinsic pathway can be induced by members of the tumor necrosis factor (TNF) family of cytokine receptors such as TNFR1 (TNF receptor-1) and Fas. The TNF family of receptors use caspase activation as a signaling mechanism, connecting ligand binding at the cell surface to the induction of apoptosis... 

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