Molecular and Functional Characterization of a Soluble Form of Oncostatin M/Interleukin-31 Shared Receptor

Abstract

Activation of the signaling transduction pathways mediated by oncostatin M (OSM) requires the binding of the cytokine to either type I OSM receptor (leukemia inhibitory factor receptor/ gp130) or to type II OSM receptor (OSMR/gp130). In the present work we have developed an enzyme-linked immunosorbent assay detecting a soluble form of OSMR (sOSMR) secreted by glioblastoma, hepatoma, and melanoma tumor cell lines. sOSMR was also present in sera of healthy individuals, with increased levels in multiple myeloma. Molecular cloning of a corresponding cDNA was carried out, and it encoded for a 70-kDa protein consisting of a half cytokine binding domain containing the canonical WSXWS motif, an immunoglobulinlike domain, and the first half of a second cytokine binding domain with cysteines in fixed positions. Analysis of the soluble receptor distribution revealed a preferential expression in lung, liver, pancreas, and placenta. sOSMR was able to bind OSM and interleukin-31 when associated to soluble gp130 or soluble interleukin-31R, respectively, and to neutralize both cytokine properties. We have also shown that OSM could positively regulate the synthesis of its own soluble receptor in tumor cells. Oncostatin M (OSM)3 was originally isolated from culture supernatant of U937 histiocytic leukemia cells based on its ability to inhibit the proliferation of the A375 melanoma cell line (1, 2). OSM is produced by activated monocyte, T lymphocyte, and dendritic cell types and is also described as a potent inducer of inflammation (3)(4)(5)(6)(7)(8). OSM belongs to the interleukin-6 cytokine family also encompassing IL-11, IL-27, leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), cardiotrophin-1, cardiotrophin-like cytokine, and neuropoietin (9 -12).The cytokines of the IL-6 family use two-or three-membrane subunit receptors to form high affinity receptor complexes able to mediate downstream signaling events (13-14). These receptors belong to the type I cytokine receptors, characterized by the presence of at least one cytokine binding domain (CBD) with conserved cysteine positions and a WSXWS motif (15). All the receptor complexes belonging to the IL-6 cytokine family share the common gp130 signaling receptor subunit in the formation of their multimeric receptors (16). Depending on the ligand, gp130 can either homodimerize in the presence of IL-6 or IL-11 (17, 18) or heterodimerize with related type I cytokine receptors such as LIFR, IL-27R, or OSMR when recruited by other members of the IL-6 family of cytokines (19 -21).In humans, OSM signal transduction occurs via two distinct receptor complexes. The type I OSM receptor consists of the low affinity chain, LIFR, associated to gp130 (19). This type I receptor can indifferently bind LIF or OSM. Through this mechanism, OSM elicits biological activities overlapping with those induced by LIF, such as hepatocyte activation, bone renewal, or the in vitro maintenance of embryonic stem cell phenotype (22).The type II OSM receptor, specifically recognizing OSM, associa...

Oncostatin-M Expression in Oral Squamous Cell Carcinoma.

“…Another potential mechanism was proposed by Kausar et al who detected a spliced variant encoding a soluble form of OSMRβ evident in esophageal cancer tissue which binds with OSM and thus acts as neutralizing receptor for OSM (12) . This hypothesis was also confirmed by Diveu et al in their study on glioblastoma (4) .…”

IL12Rβ1ΔTM Is a Secreted Product ofil12rb1That Promotes Control of Extrapulmonary Tuberculosis

“…These alternate receptor isoforms can suppress or potentiate the activity of their cognate cytokine. Suppressive isoforms include splice variants of the IL-1 receptor accessory protein (IL-1RAcP) (35), IL-1 receptor type II (IL-1RII) (36), TNF receptor 2 (TNFR2) (37), IL-4 receptor ␣ (IL4R␣) (38), leukemia inhibitory factor receptor ␣ (LIFR␣) (39), erythropoietin receptor (EPOR) (40), glycoprotein 130 (gp130) (41), IL-5 receptor ␣ (IL5R␣) (42), oncostatin M receptor (OSMR) (43), and vascular endothelial growth-factor receptor 1 (VEGFR1) (44) and receptor 2 (VEGFR2) (45). Potentiating isoforms are fewer, and include splice variants of the IL-6 receptor ␣ (IL6R␣) (46), IL-7 receptor ␣ IL12R␤1⌬TM is produced by inclusion of every il12rb1 exon but exon 14.…”

“…Bronchoalveolar lavage levels of spliced IL6R␣ are indicative of chronic lung disease in premature infants (55), while increased serum levels of spliced IL5R␣ are indicative of systemic abundance of mast cells (56). Pertaining to cancer, multiple myeloma patients have increased serum levels of spliced OSMR relative to healthy individuals (43), while an increased level of IL15R␣ in head and neck cancer patients is predictive of a poor clinical outcome (48). These studies demonstrate that, in addition to the levels of cytokines themselves, the relative levels of potentiating or suppressive receptor isoforms can also influence cytokine-driven phenomena.…”

Interleukin-31 mediates MAP kinase and STAT1/3 activation in intestinal epithelial cells and its expression is up-regulated in inflammatory bowel disease

“…However, while most colorectal cancer derived IEC expressed considerable levels of IL31Ra, its mRNA expression levels in unstimulated murine primary IEC were low suggesting that cancerogenesis might be another process in which this novel cytokine is involved. This is supported by IL31Ra expression in other malignancies such as glioblastoma and melanoma, 2 which also secrete a soluble form of OSMR which may bind IL31 when combined with soluble IL31Ra, 58 but further studies are required to elucidate potential functions of IL31 in cancerogenesis.…”