Carol A. Feghali, Ph.D., and Timothy M. Wright, M.D.

Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, E1109 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, PA 15261

Received 11/06/96; Accepted 12/13/96; On-line 01/01/97

5.1 Receptors of inflammatory cytokines:

Cytokines elicit their responses by binding to specific high affinity cell-surface receptors on target cells and initiating a series of intracellular signal transduction pathways. The receptors of several cytokines and growth factors are homologous within their extracellular domains. These receptors have been grouped into families, the largest of which is the hematopoietin receptor superfamily which includes one or multiple chains of the receptors for erythropoietin, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-11, IL-12, IL-13, IL-15, v-mpl oncogene, GM-CSF, G-CSF, prolactin, and growth hormone. The receptors in this family share a common motif of four conserved cysteine residues in the amino-terminal portion of the ligand-binding domain, as well as a conserved stretch of amino acids (WSXWS = Trp-Ser-X-Trp-Ser; X representing a nonconserved residue) proximal to the membrane-spanning region. The receptors also share fibronectin type III domains (84) (Figure 3).

FIGURE 3: Common motifs shared by the erythropoietin receptor family.

Of the above-mentioned members of the erythropoietin receptor family, one of the best characterized is the IL-2 receptor (IL-2R). It consists of three polypeptide chains: IL-2Rß (p70) and IL-2Rgamma (p64), which are expressed on resting T cells, and IL-2Ralpha (p55; T cell activation antigen or Tac), which is expressed upon T cell activation. Association of these subunits yields a high affinity receptor for IL-2 (85,86). In addition, Tac (IL-2Ralpha) is shed from cells in a soluble form, but it has low affinity for IL-2. Soluble IL-2R are elevated in the sera of patients with chronic inflammatory disorders such as rheumatoid arthritis and systemic lupus erythematosus (SLE) and the serum levels of soluble IL-2R are reported to correlate with clinical disease activity (87).

Another member of the erythropoietin receptor family, IL-6 receptor (IL-6R), consists of an 80 kDa ligand-binding molecule and a 130 kDa non-ligand binding signal-transducing subunit (gp130). Both molecules exhibit the motifs shared by members of the hematopoietin receptor superfamily (14,88). Such a bimolecular complex is also described for IL-3R, IL-5R, and GM-CSFR. For these receptors, the polypeptide beta c (KH97) is reported to be the accessory molecule (84). One of the biologic consequences of these receptor complexes is that although cytokines bind to specific receptors, some may share common pathways in eliciting the target cell's response as a result of shared receptor components. As an example, IL-6, IL-11, leukemia inhibitory factor (LIF), and oncostatin M recognize different cellular receptors (by virtue of unique ligand-binding subunits), but share the same signal-transducing receptor subunit (gp130) and similar biological activities (Figure 4). These cytokines may therefore exert their effects via common signal transduction pathways (84).

FIGURE 4: Receptors (ligand-binding subunit) and accessory molecules (non-ligand-binding signal-transducing subunit). Abbreviations: IL = Interleukin; LIF = Leukemia inhibitory factor; OSM = Oncostatin M; CNTF = Ciliary neurotrophic factor; GM-CSF = Granulocyte macrophage colony stimulating factor.

A group of receptors distantly related to the erythropoietin receptor family consists of the receptors for type I (alpha and ß) and type II (gamma) interferons (89). Receptors in this class share a homologous binding domain of about 210 amino acids and four cysteine pairs divided equally between the amino and carboxy termini.

Another group of related receptors includes the two receptors for TNF, the receptor for nerve growth factor (NGF), a transmembrane protein, FAS (Apo-1 or CD95), involved in the apoptosis of activated T lymphocytes (90), and CD40, a cell surface receptor important in B cell growth and isotype switching (91). The TNF receptors are 55 kDa (TR55) and 75 kDa (TR75) proteins that bind TNF-alpha and ß equally. Their extracellular domains share 28% identity. There is growing evidence that the two receptors may mediate different cellular responses to TNF (92,93), although there may be crosstalk between the receptors, perhaps at the level of the signalling pathways to which they are coupled.

The chemokine receptors are members of the G protein-coupled receptor (GPCR) superfamily and include IL-8R-A, an IL-8-specific receptor, IL-8R-B, a receptor recognized by IL-8, and other chemokines of the CXC subset. Recently, receptors for the CC subset of chemokines have been identified. They include CC-CKR-1, CC-CKR-2, CC-CKR-3,and CC-CKR-4 and CC-CKR-5 (94). A recently described receptor, the Duffy blood group antigen receptor for chemokines (DARC), binds both CXC and CC chemokines. In addition, the identification of new "orphan" chemokine receptors, for which no ligands have been identified, has been reported (95). Recently, five groups reported that CC-CKR-5 is a co-receptor for certain strains of HIV-1 (96). A 32-bp deletion in CKR-5 is reported to delay progression to AIDS in infected individuals and may be responsible for the antibody-negative status of individuals exposed to HIV-1 (97).