Oncostatin M and interleukin-31: Cytokines, receptors, signal transduction and physiology

Hermanns, Heike M.

doi:10.1016/j.cytogfr.2015.07.006

Cited by 202 publications

(250 citation statements)

References 167 publications

(242 reference statements)

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“…These include not only LIFR and OSMR (1,74,75) but also type I interferons (76). In the case of mOSM, our data suggest that impaired gp130 and LIFR phosphorylation may be responsible for the bias toward STAT3 signaling, but how receptor phosphorylation level is controlled remains unknown.…”

Section: Defining Mosm Action Through Mlifrmentioning

confidence: 83%

“…2 is a member of the IL-6 cytokine superfamily with a diverse range of activities (1). It was first identified as a secreted product of macrophage-like cells that inhibited proliferation of melanoma-, neuroblastoma-, and lung cancer-derived cell lines (2), and although it suppresses breast cancer cell proliferation (3), it has been suggested to support metastasis of breast cancer in the skeleton due to proosteoclastic activities (4) and to stimulate Kaposi's sarcoma (5).…”

Section: Oncostatin M (Osm)mentioning

confidence: 99%

“…Human OSM (hOSM) signals by binding first to the ubiquitously expressed glycoprotein 130 co-receptor ␣ subunit (gp130) and then recruiting, with equal affinity, either the hOSM receptor (hOSMR) or the human leukemia inhibitory factor receptor (hLIFR) ␤ subunits (14), which may then activate distinct intracellular signaling pathways (1). Murine OSM (mOSM) behaves differently with the mOSM-gp130 complex binding with high affinity to mOSMR and very low affinity to mLIFR (15).…”

Section: Oncostatin M (Osm)mentioning

confidence: 99%

See 2 more Smart Citations

Murine Oncostatin M Acts via Leukemia Inhibitory Factor Receptor to Phosphorylate Signal Transducer and Activator of Transcription 3 (STAT3) but Not STAT1, an Effect That Protects Bone Mass

Walker

Johnson

et al. 2016

Journal of Biological Chemistry

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Section: Defining Mosm Action Through Mlifrmentioning

confidence: 83%

Section: Oncostatin M (Osm)mentioning

confidence: 99%

Section: Oncostatin M (Osm)mentioning

confidence: 99%

See 1 more Smart Citation

Murine Oncostatin M Acts via Leukemia Inhibitory Factor Receptor to Phosphorylate Signal Transducer and Activator of Transcription 3 (STAT3) but Not STAT1, an Effect That Protects Bone Mass

Walker

Johnson

et al. 2016

Journal of Biological Chemistry

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“…19 OSM activates a gp130/ OSMRb receptor (OSMR) protein complex that is distinct from other IL-6 family co-receptors, which may account for the more potent OSM-induced senescence response. 26,76,77 OSMR complexes consisting of gp130/OSMRb heterodimers can activate STAT3, RAS-MAPK, and PI3K-AKT signaling, in addition to pathways not activated by other IL-6 family receptor complexes that signal via gp130/gp130 homodimers (STAT5, STAT6, AKT, and PKC-d). 19 In order to bypass the senescence program, developing cancer cells must dismantle cell cycle control by either inhibiting p16, pRb, and p53 or activating MYC (c-MYC).…”

Section: Discussionmentioning

confidence: 99%

STAT3-mediated SMAD3 activation underlies Oncostatin M-induced Senescence

et al. 2017

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Cytokines in the developing tumor microenvironment (TME) can drive transformation and subsequent progression toward metastasis. Elevated levels of the Interleukin-6 (IL-6) family cytokine Oncostatin M (OSM) in the breast TME correlate with aggressive, metastatic cancers, increased tumor recurrence, and poor patient prognosis. Paradoxically, OSM engages a tumor-suppressive, Signal Transducer and Activator of Transcription 3 (STAT3)-dependent senescence response in normal and non-transformed human mammary epithelial cells (HMEC). Here, we identify a novel link between OSM-activated STAT3 signaling and the Transforming Growth Factor-b (TGF-b) signaling pathway that engages senescence in HMEC. Inhibition of functional TGF-b/SMAD signaling by expressing a dominant-negative TGF-b receptor, treating with a TGF-b receptor inhibitor, or suppressing SMAD3 expression using a SMAD3-shRNA prevented OSMinduced senescence. OSM promoted a protein complex involving activated-STAT3 and SMAD3, induced the nuclear localization of SMAD3, and enhanced SMAD3-mediated transcription responsible for senescence. In contrast, expression of MYC (c-MYC) from a constitutive promoter abrogated senescence and strikingly, cooperated with OSM to promote a transformed phenotype, epithelial-mesenchymal transition (EMT), and invasiveness. Our findings suggest that a novel STAT3/SMAD3-signaling axis is required for OSM-mediated senescence that is coopted during the transformation process to confer aggressive cancer cell properties. Understanding how developing cancer cells bypass OSM/STAT3/SMAD3-mediated senescence may help identify novel targets for future "pro-senescence" therapies aiming to reengage this hidden tumor-suppressive response.

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“…It is produced by leukocytes, including macrophages, activated T cells and neutrophils, and acts primarily via OSM receptors on a broad range of cell types, including chondrocytes, fibroblasts, keratinocytes and endothelial cells 1, 2, to elicit diverse biological functions 3. Depending on the context, its functions include: activation of endothelium; induction of the acute phase response; induction of cellular proliferation and/or differentiation of cell types such as fibroblasts, epithelial cells and keratinocytes; modulation of erythropoiesis and megakaryopoiesis; inflammatory mediator release; and promotion of wound healing 4, 5, 6.…”

Section: Introductionmentioning

confidence: 99%

In vivo affinity and target engagement in skin and blood in a first‐time‐in‐human study of an anti‐oncostatin M monoclonal antibody

Reid

Zamuner

Edwards

et al. 2018

Brit J Clinical Pharma

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AimsThe oncostatin M (OSM) pathway drives fibrosis, inflammation and vasculopathy, and is a potential therapeutic target for inflammatory and fibrotic diseases. The aim of this first‐time‐in‐human experimental medicine study was to assess the safety, tolerability, pharmacokinetics and target engagement of single subcutaneous doses of GSK2330811, an anti‐OSM monoclonal antibody, in healthy subjects.MethodsThis was a phase I, randomized, double‐blind, placebo‐controlled, single‐dose escalation, first‐time‐in‐human study of subcutaneously administered GSK2330811 in healthy adults (NCT02386436). Safety and tolerability, GSK2330811 pharmacokinetic profile, OSM levels in blood and skin, and the potential for antidrug antibody formation were assessed. The in vivo affinity of GSK2330811 for OSM and target engagement in serum and skin blister fluid (obtained via a skin suction blister model) were estimated using target‐mediated drug disposition (TMDD) models in combination with compartmental and physiology‐based pharmacokinetic (PBPK) models.ResultsThirty subjects were randomized to receive GSK2330811 and 10 to placebo in this completed study. GSK2330811 demonstrated a favourable safety profile in healthy subjects; no adverse events were serious or led to withdrawal. There were no clinically relevant trends in change from baseline in laboratory values, with the exception of a reversible dose‐dependent reduction in platelet count. GSK2330811 exhibited linear pharmacokinetics over the dose range 0.1–6 mg kg–1. The estimated in vivo affinity (nM) of GSK2330811 for OSM was 0.568 [95% confidence interval (CI) 0.455, 0.710] in the compartmental with TMDD model and 0.629 (95% CI 0.494, 0.802) using the minimal PBPK with TMDD model.ConclusionsSingle subcutaneous doses of GSK2330811 were well tolerated in healthy subjects. GSK2330811 demonstrated sufficient affinity to achieve target engagement in systemic circulation and target skin tissue, supporting the progression of GSK2330811 clinical development.

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Oncostatin M and interleukin-31: Cytokines, receptors, signal transduction and physiology

Cited by 202 publications

References 167 publications

Murine Oncostatin M Acts via Leukemia Inhibitory Factor Receptor to Phosphorylate Signal Transducer and Activator of Transcription 3 (STAT3) but Not STAT1, an Effect That Protects Bone Mass

Murine Oncostatin M Acts via Leukemia Inhibitory Factor Receptor to Phosphorylate Signal Transducer and Activator of Transcription 3 (STAT3) but Not STAT1, an Effect That Protects Bone Mass

STAT3-mediated SMAD3 activation underlies Oncostatin M-induced Senescence

In vivo affinity and target engagement in skin and blood in a first‐time‐in‐human study of an anti‐oncostatin M monoclonal antibody

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