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OSM/OSMR and Interleukin 6 Family Cytokines in Physiological and Pathological Condition

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (10 March 2022) | Viewed by 19206

Special Issue Editor

Dr. Francesca Lantieri

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Guest Editor
Dipartimento di Scienze della Salute, Sezione di Biostatistica, Università degli Studi di Genova, 16132 Genoa, Italy
Interests: the study of human diseases through the statistical analysis of the biological and genetical data and in particular the dissection of the genetics of complex diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The interleukin-6 family is a group of cytokines with shared signaling properties, among which IL-6, Oncostatin M (OSM), leukemia inhibitory factor (LIF), and IL-31. They bind to a gp130/OSM receptor (OSMR) heterodimer complex or to a gp130/LIF receptor (LIFR) complex, while IL-31 binds to the OSMR/IL-31 receptor (IL-31R) complex. The receptor binding triggers several signaling pathways, among which Jak/STAT, the Ras-MAPK, the PI 3-K-Akt, the p38, and JNK MAPK pathways.

Both OSM and OSMR have been implicated in a variety of biological functions, including cell growth, neuronal development, and inflammatory responses. Their role has been also reported in several inflammation-related diseases and cancers and their potential as a therapy target suggested.

This Special Issue aims to uncover every aspect of IL-6 family cytokines and in particular OSM and/or OSMR functioning and signaling cascade that might unravel their role in both physiological and pathological conditions.

Dr. Francesca Lantieri
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

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Published Papers (7 papers)

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Editorial

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6 pages, 212 KiB  
Editorial
OSM/OSMR and Interleukin 6 Family Cytokines in Physiological and Pathological Condition
by Francesca Lantieri and Tiziana Bachetti
Int. J. Mol. Sci. 2022, 23(19), 11096; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911096 - 21 Sep 2022
Cited by 5 | Viewed by 1455
Abstract
Oncostatin M (OSM) is a member of the interleukin-6 (IL-6) family of cytokines and can bind two different receptors, Leukemia inhibitory factor receptor (LIFR) and Oncostatin M receptor (OSMR), through a complex containing the common glycoprotein 130 (gp130) subunit [...] Full article
(This article belongs to the Special Issue OSM/OSMR and Interleukin 6 Family Cytokines in Physiological and Pathological Condition)

Research

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12 pages, 2088 KiB  
Article
Oncostatin M Induces Lipolysis and Suppresses Insulin Response in 3T3-L1 Adipocytes
by Jennifer L. Bailey, Hardy Hang, Anik Boudreau and Carrie M. Elks
Int. J. Mol. Sci. 2022, 23(9), 4689; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23094689 - 23 Apr 2022
Cited by 2 | Viewed by 2130
Abstract
Oncostatin M (OSM) is an immune cell-derived cytokine that is upregulated in adipose tissue in obesity. Upon binding its receptor (OSMR), OSM induces the phosphorylation of the p66 subunit of Src homology 2 domain-containing transforming protein 1 (SHC1), called p66Shc, and activates the [...] Read more.
Oncostatin M (OSM) is an immune cell-derived cytokine that is upregulated in adipose tissue in obesity. Upon binding its receptor (OSMR), OSM induces the phosphorylation of the p66 subunit of Src homology 2 domain-containing transforming protein 1 (SHC1), called p66Shc, and activates the extracellular signal-related kinase (ERK) pathway. Mice with adipocyte-specific OSMR deletion (OsmrFKO) are insulin resistant and exhibit adipose tissue inflammation, suggesting that intact adipocyte OSM–OSMR signaling is necessary for maintaining adipose tissue health. How OSM affects specific adipocyte functions is still unclear. Here, we examined the effects of OSM on adipocyte lipolysis. We treated 3T3-L1 adipocytes with OSM, insulin, and/or inhibitors of SHC1 and ERK and measured glycerol release. We also measured phosphorylation of p66Shc, ERK, and insulin receptor substrate-1 (IRS1) and the expression of lipolysis-associated genes in OSM-exposed 3T3-L1 adipocytes and primary adipocytes from control and OsmrFKO mice. We found that OSM induces adipocyte lipolysis via a p66Shc-ERK pathway and inhibits the suppression of lipolysis by insulin. Further, OSM induces phosphorylation of inhibitory IRS1 residues. We conclude that OSM is a stimulator of lipolysis and inhibits adipocyte insulin response. Future studies will determine how these roles of OSM affect adipose tissue function in health and disease. Full article
(This article belongs to the Special Issue OSM/OSMR and Interleukin 6 Family Cytokines in Physiological and Pathological Condition)
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19 pages, 4420 KiB  
Article
Concomitant Activation of OSM and LIF Receptor by a Dual-Specific hlOSM Variant Confers Cardioprotection after Myocardial Infarction in Mice
by Holger Lörchner, Juan M. Adrian-Segarra, Christian Waechter, Roxanne Wagner, Maria Elisa Góes, Nathalie Brachmann, Krishnamoorthy Sreenivasan, Astrid Wietelmann, Stefan Günther, Nicolas Doll, Thomas Braun and Jochen Pöling
Int. J. Mol. Sci. 2022, 23(1), 353; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23010353 - 29 Dec 2021
Cited by 7 | Viewed by 2949
Abstract
Oncostatin M (OSM) and leukemia inhibitory factor (LIF) signaling protects the heart after myocardial infarction (MI). In mice, oncostatin M receptor (OSMR) and leukemia inhibitory factor receptor (LIFR) are selectively activated by the respective cognate ligands while OSM activates both the OSMR and [...] Read more.
Oncostatin M (OSM) and leukemia inhibitory factor (LIF) signaling protects the heart after myocardial infarction (MI). In mice, oncostatin M receptor (OSMR) and leukemia inhibitory factor receptor (LIFR) are selectively activated by the respective cognate ligands while OSM activates both the OSMR and LIFR in humans, which prevents efficient translation of mouse data into potential clinical applications. We used an engineered human-like OSM (hlOSM) protein, capable to signal via both OSMR and LIFR, to evaluate beneficial effects on cardiomyocytes and hearts after MI in comparison to selective stimulation of either LIFR or OSMR. Cell viability assays, transcriptome and immunoblot analysis revealed increased survival of hypoxic cardiomyocytes by mLIF, mOSM and hlOSM stimulation, associated with increased activation of STAT3. Kinetic expression profiling of infarcted hearts further specified a transient increase of OSM and LIF during the early inflammatory phase of cardiac remodeling. A post-infarction delivery of hlOSM but not mOSM or mLIF within this time period combined with cardiac magnetic resonance imaging-based strain analysis uncovered a global cardioprotective effect on infarcted hearts. Our data conclusively suggest that a simultaneous and rapid activation of OSMR and LIFR after MI offers a therapeutic opportunity to preserve functional and structural integrity of the infarcted heart. Full article
(This article belongs to the Special Issue OSM/OSMR and Interleukin 6 Family Cytokines in Physiological and Pathological Condition)
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19 pages, 1581 KiB  
Article
Murine Oncostatin M Has Opposing Effects on the Proliferation of OP9 Bone Marrow Stromal Cells and NIH/3T3 Fibroblasts Signaling through the OSMR
by Lena Jakob, Tony Andreas Müller, Michael Rassner, Helen Kleinfelder, Pia Veratti, Jan Mitschke, Cornelius Miething, Robert A. J. Oostendorp, Dietmar Pfeifer, Miguel Waterhouse and Justus Duyster
Int. J. Mol. Sci. 2021, 22(21), 11649; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111649 - 28 Oct 2021
Cited by 2 | Viewed by 2809
Abstract
The IL-6 family cytokine Oncostatin M (OSM) is involved in cell development, growth, hematopoiesis, inflammation, and cancer. Intriguingly, OSM has proliferative and antiproliferative effects depending on the target cell. The molecular mechanisms underlying these opposing effects are not fully understood. Previously, we found [...] Read more.
The IL-6 family cytokine Oncostatin M (OSM) is involved in cell development, growth, hematopoiesis, inflammation, and cancer. Intriguingly, OSM has proliferative and antiproliferative effects depending on the target cell. The molecular mechanisms underlying these opposing effects are not fully understood. Previously, we found OSM upregulation in different myeloproliferative syndromes. However, OSM receptor (OSMR) expression was detected on stromal cells but not the malignant cells themselves. In the present study, we, therefore, investigated the effect of murine OSM (mOSM) on proliferation in stromal and fibroblast cell lines. We found that mOSM impairs the proliferation of bone marrow (BM) stromal cells, whereas fibroblasts responded to mOSM with increased proliferation. When we set out to reveal the mechanisms underlying these opposing effects, we detected increased expression of the OSM receptors OSMR and LIFR in stromal cells. Interestingly, Osmr knockdown and Lifr overexpression attenuated the OSM-mediated effect on proliferation in both cell lines indicating that mOSM affected the proliferation signaling mainly through the OSMR. Furthermore, mOSM induced activation of the JAK-STAT, PI3K-AKT, and MAPK-ERK pathways in OP9 and NIH/3T3 cells with differences in total protein levels between the two cell lines. Our findings offer new insights into the regulation of proliferation by mOSM. Full article
(This article belongs to the Special Issue OSM/OSMR and Interleukin 6 Family Cytokines in Physiological and Pathological Condition)
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16 pages, 2186 KiB  
Article
The OSMR Gene Is Involved in Hirschsprung Associated Enterocolitis Susceptibility through an Altered Downstream Signaling
by Tiziana Bachetti, Francesca Rosamilia, Martina Bartolucci, Giuseppe Santamaria, Manuela Mosconi, Serenella Sartori, Maria Rosaria De Filippo, Marco Di Duca, Valentina Obino, Stefano Avanzini, Domenico Mavilio, Simona Candiani, Andrea Petretto, Alessio Pini Prato, Isabella Ceccherini and Francesca Lantieri
Int. J. Mol. Sci. 2021, 22(8), 3831; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22083831 - 07 Apr 2021
Cited by 7 | Viewed by 2886
Abstract
Hirschsprung (HSCR) Associated Enterocolitis (HAEC) is a common life-threatening complication in HSCR. HAEC is suggested to be due to a loss of gut homeostasis caused by impairment of immune system, barrier defense, and microbiome, likely related to genetic causes. No gene has been [...] Read more.
Hirschsprung (HSCR) Associated Enterocolitis (HAEC) is a common life-threatening complication in HSCR. HAEC is suggested to be due to a loss of gut homeostasis caused by impairment of immune system, barrier defense, and microbiome, likely related to genetic causes. No gene has been claimed to contribute to HAEC occurrence, yet. Genetic investigation of HAEC by Whole-Exome Sequencing (WES) on 24 HSCR patients affected (HAEC) or not affected (HSCR-only) by enterocolitis and replication of results on a larger panel of patients allowed the identification of the HAEC susceptibility variant p.H187Q in the Oncostatin-M receptor (OSMR) gene (14.6% in HAEC and 5.1% in HSCR-only, p = 0.0024). Proteomic analysis on the lymphoblastoid cell lines from one HAEC patient homozygote for this variant and one HAEC patient not carrying the variant revealed two well distinct clusters of proteins significantly up or downregulated upon OSM stimulation. A marked enrichment in immune response pathways (q < 0.0001) was shown in the HAEC H187 cell line, while proteins upregulated in the HAEC Q187 lymphoblasts sustained pathways likely involved in pathogen infection and inflammation. In conclusion, OSMR p.H187Q is an HAEC susceptibility variant and perturbates the downstream signaling cascade necessary for the gut immune response and homeostasis maintenance. Full article
(This article belongs to the Special Issue OSM/OSMR and Interleukin 6 Family Cytokines in Physiological and Pathological Condition)
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13 pages, 801 KiB  
Article
Transient Receptor Potential Ankyrin 1 (TRPA1) Is Involved in Upregulating Interleukin-6 Expression in Osteoarthritic Chondrocyte Models
by Elina Nummenmaa, Mari Hämäläinen, Antti Pemmari, Lauri J. Moilanen, Lauri Tuure, Riina M. Nieminen, Teemu Moilanen, Katriina Vuolteenaho and Eeva Moilanen
Int. J. Mol. Sci. 2021, 22(1), 87; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010087 - 23 Dec 2020
Cited by 20 | Viewed by 2912
Abstract
Transient receptor potential ankyrin 1 (TRPA1) is a membrane-bound ion channel found in neurons, where it mediates nociception and neurogenic inflammation. Recently, we have discovered that TRPA1 is also expressed in human osteoarthritic (OA) chondrocytes and downregulated by the anti-inflammatory drugs aurothiomalate and [...] Read more.
Transient receptor potential ankyrin 1 (TRPA1) is a membrane-bound ion channel found in neurons, where it mediates nociception and neurogenic inflammation. Recently, we have discovered that TRPA1 is also expressed in human osteoarthritic (OA) chondrocytes and downregulated by the anti-inflammatory drugs aurothiomalate and dexamethasone. We have also shown TRPA1 to mediate inflammation, pain, and cartilage degeneration in experimental osteoarthritis. In this study, we investigated the role of TRPA1 in joint inflammation, focusing on the pro-inflammatory cytokine interleukin-6 (IL-6). We utilized cartilage/chondrocytes from wild-type (WT) and TRPA1 knockout (KO) mice, along with primary chondrocytes from OA patients. The results show that TRPA1 regulates the synthesis of the OA-driving inflammatory cytokine IL-6 in chondrocytes. IL-6 was highly expressed in WT chondrocytes, and its expression, along with the expression of IL-6 family cytokines leukemia inhibitory factor (LIF) and IL-11, were significantly downregulated by TRPA1 deficiency. Furthermore, treatment with the TRPA1 antagonist significantly downregulated the expression of IL-6 in chondrocytes from WT mice and OA patients. The results suggest that TRPA1 is involved in the upregulation of IL-6 production in chondrocytes. These findings together with previous results on the expression and functions of TRPA1 in cellular and animal models point to the role of TRPA1 as a potential mediator and novel drug target in osteoarthritis. Full article
(This article belongs to the Special Issue OSM/OSMR and Interleukin 6 Family Cytokines in Physiological and Pathological Condition)
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Review

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22 pages, 2054 KiB  
Review
Stimulation of Osteoclast Formation by Oncostatin M and the Role of WNT16 as a Negative Feedback Regulator
by Pedro P. C. de Souza, Petra Henning and Ulf H. Lerner
Int. J. Mol. Sci. 2022, 23(6), 3287; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23063287 - 18 Mar 2022
Cited by 6 | Viewed by 2745
Abstract
Oncostatin M (OSM), which belongs to the IL-6 family of cytokines, is the most potent and effective stimulator of osteoclast formation in this family, as assessed by different in vitro assays. Osteoclastogenesis induced by the IL-6 type of cytokines is mediated by the [...] Read more.
Oncostatin M (OSM), which belongs to the IL-6 family of cytokines, is the most potent and effective stimulator of osteoclast formation in this family, as assessed by different in vitro assays. Osteoclastogenesis induced by the IL-6 type of cytokines is mediated by the induction and paracrine stimulation of the osteoclastogenic cytokine receptor activator of nuclear factor κ-B ligand (RANKL), expressed on osteoblast cell membranes and targeting the receptor activator of nuclear factor κ-B (RANK) on osteoclast progenitor cells. The potent effect of OSM on osteoclastogenesis is due to an unusually robust induction of RANKL in osteoblasts through the OSM receptor (OSMR), mediated by a JAK–STAT/MAPK signaling pathway and by unique recruitment of the adapter protein Shc1 to the OSMR. Gene deletion of Osmr in mice results in decreased numbers of osteoclasts and enhanced trabecular bone caused by increased trabecular thickness, indicating that OSM may play a role in physiological regulation of bone remodeling. However, increased amounts of OSM, either through administration of recombinant protein or of adenoviral vectors expressing Osm, results in enhanced bone mass due to increased bone formation without any clear sign of increased osteoclast numbers, a finding which can be reconciled by cell culture experiments demonstrating that OSM can induce osteoblast differentiation and stimulate mineralization of bone nodules in such cultures. Thus, in vitro studies and gene deletion experiments show that OSM is a stimulator of osteoclast formation, whereas administration of OSM to mice shows that OSM is not a strong stimulator of osteoclastogenesis in vivo when administered to adult animals. These observations could be explained by our recent finding showing that OSM is a potent stimulator of the osteoclastogenesis inhibitor WNT16, acting in a negative feedback loop to reduce OSM-induced osteoclast formation. Full article
(This article belongs to the Special Issue OSM/OSMR and Interleukin 6 Family Cytokines in Physiological and Pathological Condition)
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