Interleukin 6 Receptor

Tadamltsu Kishimoto, Department of Medicine III, Osaka University Medical School, 2-2 Yamada-oka, Suita-City, Osaka, Japan

The specific receptor for interleukin 6 (IL-6) was found to be expressed on lymphoid as well as non-lymphoid cells in accordance with the multifunctional properties of IL-6. Among human cell lines, IL-6 receptor is expressed on Epstein-Barr virus-transformed B cell lines (CESS, SKW-CL4), a histiocytic leukemia cell line (U937), a promyelocytic leukemia cell line (HL-60), myeloma cell lines (U266, ARH77), hepatoma cell lines (HepG2, Hep3B), and a glioblastoma cell line (SK-MG-4). In normal tissues, IL-6 receptor is expressed on hepatocytes and monocytes, not on resting B cells but on activated large B cells with IgD negative phenotype, and on CD4 7CD8 as well as CD4 7CD8+ T cells (in the case of T cells, no significant change after phytohem-agglutinin (PHA) stimulation). The number of receptors on each cell is relatively small; i.e. 100-20 000. Scatchard plot analysis demonstrated the presence of high- and low-affinity IL-6 binding sites -Kj = 10"" m and 10~9m respectively. The number of high-affinity sites is usually 5-10% of the total binding sites.

Complementary DNA encoding human IL-6 receptor capable of expressing both high- and low-affinity binding sites has been cloned. Human IL-6 receptor consists of 468 amino acids (a.a.), -19 a.a. signal peptide, -339 a.a. extracellular portion, -28 a.a. transmembrane domain, -82 a.a. intracytoplasmic portion. There are six potential N-linked glycosyl-ation sites (Asn-X-Ser/Thr) and 11 cysteine residues. The mature receptor has O- and /V-glycosylauon and its molecular weight is about 80 kDa.

Inspection of the IL-6 receptor sequence shows that the region between position -20 and -110 fulfills the criteria for the constant 2 (C2) set of the immunoglobulin (Ig) superfamily. The extracellular region following the C2 set domain has homology with the extracellular portion of IL-2 receptor (3 chain, IL-3 receptor, IL-4 receptor, IL-7 receptor, growth hormone receptor, and erythropoietin receptor (a cytokine receptor family having four cysteines and the motif Trp-Ser-X-Trp-Ser). The intracytoplasmic portion of IL-6 reccptor is short and has no tyrosine kinase domain, unlike certain other growth factor receptors, and shows no homology with other known functional proteins. Thus it indicates that transduction of the IL-6 signal could be mediated through another molecule associated with the IL-6 receptor.

The mouse IL-6 receptor has 460 amino acid residues and has homology to the human receptor over its whole sequence.

When the IL-6 receptor was precipitated with monoclonal anti-IL-6 receptor antibody under mild lysis (1% digitonin), only the 80 kDa IL-6 receptor molecule was observed. Another polypeptide chain of 130 kDa was coprecipitated with IL-6 receptor, when the cells were incubated with IL-6 at 37°C for 30 min before digitonin lysis. This observation suggested that IL-6 triggered the association of the 80 kDa IL-6 receptor with a 130 kDa molecule. This 130 kDa molecule was a membrane-anchored glycoprotein (gpl30), since it was labeled when labeling the cell surface and its molecular weight was decreased by glycanase treatment.

The murine gpl30 homolog could be associated with the human IL-6 receptor by IL-6 stimulation, using a mouse transfectant with human IL-6 receptor cDNA. gpl30 alone cannot bind IL-6 if the parental cell line has no IL-6-binding sites.

The murine myeloid cell line Ml transfected with either normal human IL-6 receptor cDNA or deletion mutant IL-6 receptor cDNA lacking the intracyto-plasmic portion was growth inhibited and induced to differentiate to macrophages by IL-6 stimulation. This result indicates that the intracytoplasmic portion of IL-6 receptor is not required for the signal transduction.

Soluble IL-6 receptor lacking the transmembrane and cytoplasmic domains could associate with gpl30 in the presence of IL-6 and provide the IL-6 signal.

These results show that the IL-6 receptor system is composed of two functional chains, the ligand-binding 80 kDa IL-6 receptor and the nonligand binding gpl30. Interleukin 6 triggers the association of IL-6 receptor and gpl30 on the cell membrane and gp!30 provides the IL-6 signal. gpl30 functions as a signal transducer not only for IL-6 but also for various cytokines belonging to the IL-6 family, such as LIF, CNTF, oncostatinM, IL-11 and cardiotro-phin. Homodimerization of gpl30 or heterodimeriz-ation of gpl30 and LIF receptor activates the JAK-STAT3 signaling pathway.

See also: Cytokine receptors; Immunoglobulin gene superfamily; Interleukin 6.

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