Expression cloning of a human IL-12 receptor component. A new member of the cytokine receptor superfamily with strong homology to gp130.

Abstract

A cDNA encoding a human IL-12R subunit was isolated by expression cloning. This subunit is a 662 amino acid type I transmembrane protein with an extracellular domain of 516 amino acids and a cytoplasmic domain of 91 amino acids. It is a member of the hemopoietin receptor superfamily and is most closely related over its entire length to gp130 and the receptors for granulocyte-CSF (G-CSF) and leukemia-inhibitory factor. When expressed in COS cells, this IL-12R subunit binds both human and murine IL-12 with an apparent affinity of 2 to 5 nM. The transfected COS cells express both monomers and disulfide-linked dimers or oligomers of the IL-12R subunit on their surface. However, unlike the IL-6-induced dimerization of gp130, the oligomerization of the IL-12R subunit is not dependent on binding of IL-12. Only the IL-12R subunit dimers/oligomers but not the monomers bind IL-12 with an affinity of 2 to 5 nM. A polyclonal antiserum raised against this receptor subunit specifically inhibits IL-12-induced proliferation of PHA-activated PBMC. The data are consistent with the hypotheses that 1) a dimer/oligomer of the cloned IL-12R subunit (IL-12R-beta) represents the low affinity IL-12 binding site identified on human lymphoblasts, 2) the cloned receptor subunit is involved in IL-12 signal transduction, and 3) an additional, as of yet unidentified subunit is required to generate a high affinity IL-12R complex.

Human IL-35 Inhibits the Bioactivity of IL-12 and Its Interaction with IL-12Rβ2

“…Second, and per the early studies of IL-12R signaling done at Hoffman-LaRoche (reviewed in Ref. 16 ), IL-12Rβ1 oligomers (not monomers) bind IL-12 ( 60 ), and, although IL-12Rβ1, which is homologous to gp130, primarily binds to IL-12 via its IL-12p40 domain, it nevertheless makes contact with the IL-12p35 domain per structural modeling studies ( 61 ). In IL-35 HI conditions, the IL-12p35 domain of IL-35 may be interacting with the IL-12Rβ1 oligomers that surround IL-12, triggering the activity of their associated intracellular kinases ( 62 ).…”

Selectivity, efficacy and safety of JAKinibs: new evidence for a still evolving story

“…Signalling in response to binding of IL-6, IL-11, IL-13, oncostatin M and leukaemia inhibitory factor to the type I receptor common gp130 chain is mediated through JAK1 and JAK2, although some data point to a role for TYK2 as well18; together these signals lead to a combination of STAT3 and STAT1 activation 19. IL-12 and IL-23 activate specific receptor complexes that share the common p40 receptor chain and bind JAK2 and TYK2, which leads to the activation of STAT3 and STAT4 20–23. Receptors for IL-3, IL-5 and granulocyte macrophage colony-stimulating factor (GM-CSF), as well as erythropoietin (EPO), thrombopoietin (TPO) and granulocyte colony-stimulating factor (G-CSF) signal solely via JAK2 and lead to STAT5 phosphorylation 24…”

“…19 IL-12 and IL-23 activate specific receptor complexes that share the common p40 receptor chain and bind JAK2 and TYK2, which leads to the activation of STAT3 and STAT4. [20][21][22][23] Receptors for IL-3, IL-5 and granulocyte macrophage colony-stimulating factor (GM-CSF), as well as erythropoietin (EPO), thrombopoietin (TPO) and granulocyte colony-stimulating factor (G-CSF) signal solely via JAK2 and lead to STAT5 phosphorylation. 24 The type II receptor subfamily comprises the IL-10 and interferon (IFN) cytokine families.…”