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m receptors can endow them with responsiveness to IL-6, CNTF or LPS.

5. Receptors that gain novel ligand activity upon their shedding (Figure 1(5)) Such a situation seems to exist in the case of the soluble form of CD23. In its cell-bound form, this type II transmembrane protein acts as a low-affinity receptor for IgE and also binds a cell surface protein, CD21. In its soluble form, CD23 was reported to have a variety of cytokine effects on cells. Some seem to be due to triggering of 'reversed signaling' by CD21. Others, however, seem to be mediated by another, as yet undefined, receptor. The cytokine effects of the soluble CD23 molecules are mediated by an epitope distinct from the IgE-binding site.

6. Receptors which, when in soluble form, can serve functions unrelated to signaling (Figure 1(6)) The only known example of SRs that act in this way is provided by the immunoglobulins. In their cell surface form, these molecules initiate signaling activities within the cells that express the receptors (B lymphocytes). In their soluble form, on the other hand, the immunoglobulins modulate the function of the antigens to which they bind by neutralizing or opsonizing them, by facilitating their transport, or -in the case of antigens that are expressed on the surface of cells — by causing their destruction (through effects of complement or of antibody-dependent cellular cytotoxicity). These modulatory functions are exerted through binding activities of C-terminal regions unique to the soluble immunoglobulins (the Fc region). An example of the unique binding ability of the Fc region is seen in its ability to bind to specific Fc receptors.

In vivo function

As mentioned above, there is still hardly any direct information on the in vivo significance of the SRs. In the absence of such information, one cannot exclude the possibilities that at least some of the SRs have no functional significance at all, or (in the case of SRs that are derived proteolytically from the cell-bound forms) are merely side-products of the down-regulation of cell surface receptors upon their cleavage. A major obstacle to objective evaluation of the functional significance of SRs is the lack of technical tools for evaluating the impact of specific elimination of these molecules. Use of knockout mice or neutralizing antibodies, which have proved very useful in evaluating the in vivo relevance of the cytokines, cannot be applied in studies of the function of their SRs unless a way is found to maintain the function of the cell surface receptors while eliminating or blocking the soluble forms. There are, however, a few noteworthy items of indirect evidence which suggest that SRs have important functions in vivo-.

1. Assessment of the effect of human sera on the in vitro function of TNF confirmed that the soluble TNF receptors reach serum levels that are high enough to effectively suppress TNF effects (at the TNF concentrations attained in the serum).

2. Deletion of the genes that encode viroceptors resulted in significant reduction of the pathogenesis of the viruses that harbor these genes, confirming that the viroceptors act to suppress immunoprotective effects of cytokines.

3. As mentioned above, the soluble IL-6 receptor can substitute for the cell surface IL-6 receptor. The physiological significance of this mode of action of SRs is supported by findings about the structure of IL-12. This cytokine is composed of two subunits that show considerable sequence similarity to IL-6 and its soluble receptor, and probably act together in a way analogous to that of the IL-6-IL-6 SR complex.

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