Functions of soluble receptors

Current ideas of the function of SRs are largely speculative, being based primarily on in vitro effects of these molecules and only to a small extent on direct information about their in vivo effects.

In vitro effects

In vitro studies of SRs have revealed several different potential roles of these molecules.

1. SRs that may act as inhibitors of signaling (Figure 1(1)) All SRs bind their ligands with lower affinity than that of their cell surface forms. The binding affinity of some, for example the soluble IL-2Ra, is rather low, raising doubts as to their ability to affect significantly the function of the cell surface receptors. Other SRs, however (e.g. the receptors for IL-1, IL-4 or TNF), have binding affinities high enough to allow them to compete effectively with the cell surface receptors for the ligands. Except in cases where the SRs themselves have the ability to act as initiators of signaling (see below), binding of the ligand to such SRs is expected to result in blockage of signaling.

2. SRs that may act as inhibitors of reversed signaling (Figure 1(2)) Although not documented so far, it is possible in theory that the SRs may also act as inhibitors of 'reversed signaling'. As illustrated in Figure 1(2), in the case of cell surface ligand molecules that exhibit reversed signaling (when aggre gated as a consequence of their binding to the cell surface receptors), binding of the monomeric SR molecules to the ligand may impede the ligand's interaction with the cell surface receptors and thus block signaling.

3. SRs that may assist the function of their ligands (Figure 1(3)) IL-4 dissociates from its SR much more rapidly than from its cell surface receptors. The soluble IL-4 receptors also provide 11.-4 with protection against proteolytic degradation. Therefore, although at high concentrations these receptors can interfere with IL-4 function, it seems likely that at their physiological levels the soluble IL-4 receptors actually serve as carriers of IL-4 in the circulation and facilitate its presentation to the cell-bound receptors. A similar role was ascribed to the soluble form of the growth hormone receptor (the growth hormone-binding protein). This SR is believed to increase the functional duration of its ligand by withholding its clearance from the circulation. The soluble TNF receptors are also found to increase the functional duration of their ligands, though by a different mechanism: they prevent dissociation of the trimeric TNF molecules into inactive monomers and thus, despite their ability to compete with the cell surface TNF receptors for TNF binding, they augment those TNF effects that are slowly induced. The fact that SRs can have such positive effects on ligand function, as well as the consistent occurrence of some SRs in body fluids and the existence of mechanisms that coordinate the extent of SR formation with that of their ligands, suggests that some SRs may play an integral role (as 'buffers' or carriers) in the normal functioning of their ligands.

4. SRs that can substitute for the cell-surface receptors (Figure 1(4)) The a chain of the IL-6 receptor is devoid of signaling activity. After ligand binding, however, it associates with another transmembrane protein, gpl30 (which constitutes the /3 chain of the IL-6 receptor as well as of other receptors of the II-6 family); and the latter initiates signaling within the cell. In this case, the soluble forms of the two components of the receptors affect ligand function in opposite ways. The soluble form of gp130 blocks the function of IL-6 (as well as of the other cytokines that employ gpl30 as part of their receptors). The soluble form of the a chain of the IL-6 receptor, however, can substitute for the cell surface receptor. The situation is similar in the case of the CNTF-R and CD14, a cell-surface lipopolysaccharide (LPS)-binding protein. Application of the soluble forms of the IL-6 receptor a chain, CNTF-R or CD 14 to cells that do not express the cell surface forms of the

Table 1 Examples of known soluble forms of receptors, their presumed functions and mechanisms of formation

Receptor Structural motifs in extracellular domain (receptor family)

Function of cell surface form

Soluble form

Presumed function

Mechanism of formation

Proteolytic Lack of GPI Specific Specific cleavage anchorage/PLC transcripts transcripts cleavage of GPI allowing cleavage

IL-1, type 1-R IL-1, type ll-R IL-2R« IL-2Rß IL-4R

Ciliary neurotrophic factor (CNTF)-Ra

Immunoglobulin-like domain

Immunoglobulin-like domain

Two CCP domains

Cytokine receptor and fibronectin type II domains Cytokine receptor and fibronectin type II domains

Cytokine receptor and fibronectin type II domains

Immunoglobulin-like, cytokine receptor, and fibronectin type II domains Immunoglobulin-like, cytokine receptor domain, cytokine receptor motif and four fibronectin type III domains Class I cytokine receptor, GPI anchored

Growth hormone-R Class I cytokine receptor

Inflammatory and acute phase reactions. Thymocyte and T cell activation 'Decoy' receptor (blocks llgand binding to coexpressed type I receptor) T and B cell growth, macrophage activation

T and B cell growth, macrophage and natural killer activation Regulation of allergic reactions, lgG1 and IgE responses, growth and differentiation of hematopoietic cells, suppression of macrophage-mediated immune functions Growth and differentiation of eosinophils and B and T lymphocytes

Acute phase protein induction, stimulation of growth of activated mature B lymphocytes, regulation of Inflammation Acute phase protein induction, regulation of growth and differentiation of cells through effects of the various IL-6 subfamily receptors Growth and differentiation of cells of the neuronal system

Bone growth, lactogenic, insulin-like, diabetogenic, lipolytic, protein-anabolic and sodium/water-retaining effects

Blocks ligand binding

Blocks ligand binding

Blocks ligand binding

Blocks ligand binding

Blocks ligand binding? 'Transport' molecule?

Blocks ligand binding

Signals (substitutes for the cell surface receptor)

Blocks ligand binding to the various IL-6 subfamily receptors

Blocks ligand binding (substitution for the cell surface receptor)

Decreases rate of clearance of the ligand from the circulation

TNF, p55R (CD120a) TNF, p75R (CD120b)

TNF/NGF receptor family TNF/NGF receptor family

Fas/Apo-1 (CD95) TNF/NGF receptor family NGF, p75R TNF/NGF receptor family

IFNa-R (IFNAR-2) Class II cytokine receptor IFN-y-R Class II cytokine receptor

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