Investigations of the IL-6R system have provided evidence that a complex of IL-6 and a soluble form of IL-6Ra could act on the cells that express gp130, but not the a-chain. This kind of model can apply to other cytokine receptor systems. IL-12 consists of a disulfide heterodimer of 40kD (p40) and 35kD (p35) subunits (93). The peptide sequences of p35 and p40 resemble IL-6 and the soluble form of its receptor, respectively (94), suggesting that IL-12 acts on target cells in a manner similar to the complex of IL-6 and soluble IL-6R. This model is also supported by the fact that molecular cloning of IL-12R showed that it is a member of the cytokine receptor super family, most closely related to gp130 (95). Another example is a CNTFRa that is anchored to the cell membrane by a glycosyl-phosphatidyl inositol (GPI) linkage. The complex of soluble CNTFRa and CNTF acts on the cells that express LIFRb and gp130 (96). Potential physiological roles for the soluble CNTFRa are suggested by the presence of the soluble form of the a-chain in cerebrospinal fluid and its release from skeletal muscle in response to peripheral nerve injury.
Based on these facts, I originally proposed a novel mechanism by which the cytokine system generates functional diversity (Figure 3) (24). A complex consisting of a soluble cytokine receptor and its corresponding cytokine acquires a different target specificity from the original cytokine and, therefore, it should express functions distinct from the original cytokine. Actually, double transgenic mice expressing human IL-6 and IL-6Ra showed myocardial hypertrophy (97), indicating that the complex of IL-6 and the soluble form of IL-6Ra acts on heart muscle cells that express gp130, on which IL-6 alone cannot act, leading to the induction of cardiac hypertrophy similar to the effect of CT-1. This model could also be applied to the glial-cell-line-derived neurotrophic factor (GDNF) receptor system, which consists of a GDNF-specific binding molecule, GDNFRa, which is a GPI-anchored membrane molecule, and a signal transducing GDNFR, Ret, which is a receptor tyrosine kinase (98,99). I anticipate that this novel mechanism will be applied to a wide range of other receptor systems. This mechanism may contribute to generating the functional diversity of cytokines and may also play pathological roles in various diseases, since an increase in the serum-soluble form of various cytokine receptors has been reported to occur in a variety of diseases.
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