Gpl30 cytokines

Interleukin-6 (IL-6) is a member of the gpl30 cytokine family and is con-stitutively produced by several cells of bone microenvironment, particularly by osteoblasts and their precursors (Heymann et al. 2000). The main function in bone is on OCS and bone resorption, and its effects are connected to those of IL-1, TNF-a, and PTHrP. IL-6 induces osteoclastlike formation by inducing IL-1 synthesis, and the addition of anti-IL-1 inhibits osteoclast formation by IL-6 (Kurihara et al. 1990). Moreover, IL-6 mediates the effects of TNF-a and enhances PTHrP-induced hypercalcemia and bone resorption by increasing the osteoclast progenitor pool and differentiation into mature osteoclasts (Devlin et al. 1998). 

Heymann D, Rousselle AV (2000) gpl30 Cytokine family and bone cells. Cytokine 12 1455-1468... 

Arzt, E. (2001) gpl30 cytokine signaling in the pituitary gland a paradigm for cytokine-neuro-endocrine pathways. J.Clin.Invest, 108, 1729-1733. 

The three-dimensional structures are known for many gpl30 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)... 

LIF receptor also uses its Ig domain (D3) to receive site III epitopes of CNTF, LIF, CT-1, OSM, and others. So the Ig domain of LIF receptor is, in fact, more cross-reactive than gpl30. The site III structures of all gpl30-cytokines maintain a conserved aromatic residue at the tip of the D helix (Fig. 7) that is certainly the structural analog to the Trp residues we see in the center of the gplSO site III interface. Therefore we predict that the LIFR site III interface cross-reactivity is achieved by using similar structural features at the gpl30 IgD. 

STPs (2). Class 1 cytokine receptors interact with three different STPs (gpl30. Pc. and Yc). The STPs themselves do not bind cytokines, but conduct the signal to tyrosine kinases (3). The fact that different cytokines can activate the same STP via their receptors explains the overlapping biological activity of some cytokines. 

Figure 4.1. Cytokine receptors usually display a unique cytokine ( ligand )-binding domain, but share additional receptor components, which are normally responsible for signal transduction. This explains the molecular basis of pleiotropy. IL-6, IL-11 and leukaemia inhibitory factor (LIF), for example, are all composed of a distinct ligand-specific binding domain, and a separate subunit (gpl30). gpl30 is responsible for initiating signal transduction and is identical in all three receptors. This is depicted schematically above...

Fig. 11.3. Subunit structures of cytokine receptors. EpoR and G-CSFR have a homo-oligomeric structure. The other receptors shown are composed of different subunits, some of which occur in several receptors. The gpl30 subunit is common to IL-6R and LIF-R the Yc subunit is found in IL-2R and IL-4R. The subunits, at which ligand binding occurs, are indicated by arrows. LIF-R leukemia inhibitory factor receptor.

The presence of at least two chains is the common characteristic of many of these receptors. The cytokines having two chain structures exhibit dual affinity although there are some exceptions. The examples of receptors with two chain structures include sharing of y-y subunit of IL-2with IL-4, IL-7, IL-9, IL-15 and IL-21, common (3 chains of IL-3, IL-5 and GM-CSF and common a chain for IL-4 and IL-13. gpl30, which is a second chain required for IL-6-a activity, is also a trigger for several other cytokines. The binding of the cytokine to the double chain renders a dual affinity as is the case for IL-2, IL-3, IL-5, IL-7 and GM-CSF. 

Heinrich PC, Behrmann I, Muller-Newen G, Schaper F, Graeve L. 1998. Interleukin-6 type cytokine signaling through the gpl30/JAK/STAT pathway. Biochem J. 334 297-314. 

Cytokine subfamily 2 includes proteins with heterodimeric a—(3 or ct-gpl30 receptors. Thus, granulocyte macrophage colony stimulating factor (GM-GSF), IL-3 and IL-5 act via a—(3 receptors and share (3 receptors. Cardiotrophin-1 (GT-1), ciliary neurotrophic factor (CTNF), IL-6, IL-1, leukaemia inhibitory factor (LIF) and oncostatin M (OSM) act via heterodimeric a-gpl30 receptors with a shared gpl30 receptor subunit. Leucocyte-derived cytokines of this family have immunomodulatory and haematopoietic effects. 

Cross-Reactivity of the gpl30 IGD with Cytokine Site III. 132... 

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.)...

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