Gp130 Cytokine Research Articles

Structural plasticity of human leptin binding to its receptor LepR

Leptin receptor (LepR) signaling plays an essential role in balancing food intake and energy expenditure. The architecture of LepR signaling assembly is critical for its function. In this study, we determined the structures of three distinct conformations of human leptin–LepR using cryo-electron microscopy at resolutions of 3.88, 3.77, and 3.58 Å. Both 2:2 and 3:3 stoichiometric assemblies were observed, and the complexes exhibited asymmetric open conformations. Leptin undergoes substantial rearrangement of its flexible regions to accommodate binding to LepR. The assembled leptin–LepR complexes connect through a “hand-in-hand” geometry. The open, interlocked 3:3 trimeric assembly results from the engagement of a third leptin–LepR heterodimer with a 2:2 dimer. The asymmetric geometry of LepR is substantially distinct from that of other gp130 cytokine homologs, and that may be due to the twisted and rigid interface between the D3 and D4 domains. These results highlight the distinct engagement of leptin with LepR and provide important insights into the structural plasticity of LepR-signaling assemblies.

Type I Interferon Signaling is Required for Oncostatin-M Driven Inflammatory Responses in Mouse Lung

Type I interferons (IFNs) consist of a group of structurally similar cytokines that play an integral role in regulating the immune response to combat lung infections. In certain models type I IFNs have also been associated with suppression of Th2-skewed immune and inflammatory responses. Transient pulmonary overexpression of the gp130 cytokine Oncostatin M (OSM) by Adenovirus vector (AdOSM) induces a robust Th2-skewed cytokine/inflammatory profile in C57Bl/6 murine lungs. In this study we assessed type I IFN function in OSM-mediated inflammation in vivo using Ifnar1-/- C57Bl/6 mice and Ifnar1-deficient cells in vitro. Ifnar1-/- mice showed a significant reduction in AdOSM-induced histopathology (epithelial hyperplasia, alveolar septal wall thickening, cellular infiltration), and levels of IL-6 and chemokine protein (CXCL-1/KC and CCL24/eotaxin-2) in lungs compared with wild-type. Ifnar1-/- murine fibroblasts and human type I IFN receptor (Ifnar)-knockdown fibroblasts were also less responsive to OSM in STAT3 activation and cytokine production compared with Ifnar-sufficient cells in vitro. Exogenous type I IFN induced IL-6 responses in mouse and human fibroblasts and in combination with OSM further stimulated IL-6 production, suggesting a concerted action of type I IFNs and OSM. Taken together, these results demonstrate that cross-talk between IFNAR and OSM signaling enhances cell responses and modulates OSM-driven responses in lung inflammation.

Analyses of the complex formation of staphylococcal enterotoxin A and the human gp130 cytokine receptor.

Superantigens (SAgs) are bacterial enterotoxins produced by Staphylococcus aureus. Staphylococcal enterotoxin type A (SEA), a staphylococcal superantigen, has been shown to bind to the cytokine signalling receptor glycoprotein 130 (gp130). The structural details, as well as the exact physiological role of this interaction, remain unclear. Here, we describe the structural details of the SEA-gp130 complex by combining crosslinking mass spectrometry and computational modelling. Interestingly, SEA is not able to bind gp130-homologues from rat and mouse. Our data suggest that SEA may interact with human gp130 in a different manner than other known gp130-ligands. Moreover, the fact that SEA does not bind mouse or rat gp130 suggests that SAgs have additional mechanisms of action in humans.

Pleiotropic Effect of IL-6 Produced by B-Lymphocytes During Early Phases of Adaptive Immune Responses Against TB Infection.

The role of B cells migrating to the lung and forming follicles during tuberculosis (TB) inflammation is still the subject of debate. In addition to their antibody production and antigen-presenting functions, B cells secrete different cytokines and chemokines, thus participating in complex networks of innate and adaptive immunity. Importantly, lung B-cells produce high amounts of the pleiotropic gp130 cytokine IL-6. Its role during TB infection remains controversial, partly due to the fact that IL-6 is produced by different cell types. To investigate the impact of IL-6 produced by B cells on TB susceptibility and immune responses, we established a mouse strain with specific IL-6 deficiency in B cells (CD19cre-IL-6fl/fl, B-IL-6KO) on the B6 genetic background. Selective abrogation of IL-6 in B cells resulted in shortening the lifespan of TB-infected B-IL-6KO mice compare to the wild-type controls. We provide evidence that at the initial TB stages B cells serve as a critical source of IL-6. In the lung, the effect of IL-6 deficiency in B cells is associated rather with B and T cell functioning, than with macrophage polarization. TB-infected B-IL-6KO mice displayed diminished sizes of B cells themselves, CD4+IFN-γ+, Th17+, and CD4+CXCR5+ follicular T cell populations. The pleiotropic effect of B-cell-derived IL-6 on T-cells demonstrated in our study bridges two major lymphocyte populations and sheds some light on B- and T-cells interactions during the stage of anti-TB response when the host switches on a plethora of acquired immune reactions.

Oncostatin M suppresses browning of white adipocytes via gp130-STAT3 signaling

ObjectiveObesity is associated with low-grade adipose tissue inflammation and locally elevated levels of several glycoprotein 130 (gp130) cytokines. The conversion of white into brown-like adipocytes (browning) may increase energy expenditure and revert the positive energy balance that underlies obesity. Although different gp130 cytokines and their downstream targets were shown to regulate expression of the key browning marker uncoupling protein 1 (Ucp1), it remains largely unknown how this contributes to the development and maintenance of obesity. Herein, we aim to study the role of gp130 cytokine signaling in white adipose tissue (WAT) browning in the obese state. MethodsProtein and gene expression levels of UCP1 and other thermogenic markers were assessed in a subcutaneous adipocyte cell line, adipose tissue depots from control or adipocyte-specific gp130 knockout (gp130Δadipo) mice fed either chow or a high-fat diet (HFD), or subcutaneous WAT biopsies from a human cohort of lean and obese subjects. WAT browning was modeled in vitro by exposing mature adipocytes to isoproterenol after stimulation with gp130 cytokines. ERK and JAK-STAT signaling were blocked using the inhibitors U0126 and Tofacitinib, respectively. ResultsInguinal WAT of HFD-fed gp130Δadipo mice exhibited significantly elevated levels of UCP1 and other browning markers such as Cidea and Pgc-1α. In vitro, treatment with the gp130 cytokine oncostatin M (OSM) lowered isoproterenol-induced UCP1 protein and gene expression levels in a dose-dependent manner. Mechanistically, OSM mediated the inhibition of Ucp1 via the JAK-STAT but not the ERK pathway. As with mouse data, OSM gene expression in human WAT positively correlated with BMI (r = 0.284, p = 0.021, n = 66) and negatively with UCP1 expression (r = −0.413, p < 0.001, n = 66). ConclusionsOur data support the notion that OSM negatively regulates thermogenesis in WAT and thus may be an attractive target for treating obesity.

WNT16 is Robustly Increased by Oncostatin M in Mouse Calvarial Osteoblasts and Acts as a Negative Feedback Regulator of Osteoclast Formation Induced by Oncostatin M

BackgroundBone loss is often observed adjacent to inflammatory processes. The WNT signaling pathways have been implicated as novel regulators of both immune responses and bone metabolism. WNT16 is important for cortical bone mass by inhibiting osteoclast differentiation, and we have here investigated the regulation of WNT16 by several members of the pro-inflammatory gp130 cytokine family.MethodsThe expression and regulation of Wnt16 in primary murine cells were studied by qPCR, scRNAseq and in situ hybridization. Signaling pathways were studied by siRNA silencing. The importance of oncostatin M (OSM)-induced WNT16 expression for osteoclastogenesis was studied in cells from Wnt16-deficient and wild-type mice.ResultsWe found that IL-6/sIL-6R and OSM induce the expression of Wnt16 in primary mouse calvarial osteoblasts, with OSM being the most robust stimulator. The induction of Wnt16 by OSM was dependent on gp130 and OSM receptor (OSMR), and downstream signaling by the SHC1/STAT3 pathway, but independent of ERK. Stimulation of the calvarial cells with OSM resulted in enhanced numbers of mature, oversized osteoclasts when cells were isolated from Wnt16 deficient mice compared to cells from wild-type mice. OSM did not affect Wnt16 mRNA expression in bone marrow cell cultures, explained by the finding that Wnt16 and Osmr are expressed in distinctly different cells in bone marrow, nor was osteoclast differentiation different in OSM-stimulated bone marrow cell cultures isolated from Wnt16−/- or wild-type mice. Furthermore, we found that Wnt16 expression is substantially lower in cells from bone marrow compared to calvarial osteoblasts.ConclusionThese findings demonstrate that OSM is a robust stimulator of Wnt16 mRNA in calvarial osteoblasts and that WNT16 acts as a negative feedback regulator of OSM-induced osteoclast formation in the calvarial bone cells, but not in the bone marrow.

New insights into IL-6 family cytokines in metabolism, hepatology and gastroenterology.

IL-6 family cytokines are defined by the common use of the signal-transducing receptor chain glycoprotein 130 (gp130). Increasing evidence indicates that these cytokines are essential in the regulation of metabolic homeostasis as well as in the pathophysiology of multiple gastrointestinal and liver disorders, thus making them attractive therapeutic targets. Over the past few years, therapies modulating gp130 signalling have grown exponentially in several clinical settings including obesity, cancer and inflammatory bowel disease. A newly engineered gp130 cytokine, IC7Fc, has shown promising preclinical results for the treatment of type 2 diabetes, obesity and liver steatosis. Moreover, drugs that modulate gp130 signalling have shown promise in refractory inflammatory bowel disease in clinical trials. A deeper understanding of the main roles of the IL-6 family of cytokines during homeostatic and pathological conditions, their signalling pathways, sources of production and target cells will be crucial to the development of improved treatments. Here, we review the current state of the role of these cytokines in hepatology and gastroenterology and discuss the progress achieved in translating therapeutics targeting gp130 signalling into clinical practice.

Context-aware synthetic biology by controller design: Engineering the mammalian cell.

The rise of systems biology has ushered a new paradigm: the view of the cell as a system that processes environmental inputs to drive phenotypic outputs. Synthetic biology provides a complementary approach, allowing us to program cell behavior through the addition of synthetic genetic devices into the cellular processor. These devices, and the complex genetic circuits they compose, are engineered using a design-prototype-test cycle, allowing for predictable device performance to be achieved in a context-dependent manner. Within mammalian cells, context effects impact device performance at multiple scales, including the genetic, cellular, and extracellular levels. In order for synthetic genetic devices to achieve predictable behaviors, approaches to overcome context dependence are necessary. Here, we describe control systems approaches for achieving context-aware devices that are robust to context effects. We then consider cell fate programing as a case study to explore the potential impact of context-aware devices for regenerative medicine applications.

Functional and structural analysis of cytokine-selective IL6ST defects that cause recessive hyper-IgE syndrome

Biallelic variants in IL6ST, encoding GP130, cause a recessive form of hyper-IgE syndrome (HIES) characterized by high IgE level, eosinophilia, defective acute phase response, susceptibility to bacterial infections, and skeletal abnormalities due to cytokine-selective loss of function in GP130, with defective IL-6and IL-11 and variable oncostatin M (OSM) and IL-27levels but sparing leukemia inhibitory factor (LIF) signaling. Our aim was to understand the functional and structural impact of recessive HIES-associated IL6ST variants. We investigated a patient with HIES by using exome, genome, and RNA sequencing. Functional assays assessed IL-6, IL-11, IL-27, OSM, LIF, CT-1, CLC, and CNTF signaling. Molecular dynamics simulations and structural modeling of GP130 cytokine receptor complexes were performed. We identified a patient with compound heterozygous novel missense variants in IL6ST (p.Ala517Pro and the exon-skipping null variant p.Gly484_Pro518delinsArg). The p.Ala517Pro variant resulted in a more profound IL-6- and IL-11-dominated signaling defect than did the previously identified recessive HIES IL6ST variants p.Asn404Tyr and p.Pro498Leu. Molecular dynamics simulations suggested that the p.Ala517Pro and p.Asn404Tyr variants result in increased flexibility of the extracellular membrane-proximal domains of GP130. We propose a structural model that explains the cytokine selectivity of pathogenic IL6ST variants that result in recessive HIES. The variants destabilized the conformation of the hexameric cytokine receptor complexes, whereas the trimeric LIF-GP130-LIFR complex remained stable through an additional membrane-proximal interaction. Deletion of this membrane-proximal interaction site in GP130 consequently caused additional defective LIF signaling and Stüve-Wiedemann syndrome. Our data provide a structural basis to understand clinical phenotypes in patients with IL6ST variants.

STAT3 Signalling via the IL-6ST/gp130 Cytokine Receptor Promotes Epithelial Integrity and Intestinal Barrier Function during DSS-Induced Colitis.

The intestinal epithelium provides a barrier against commensal and pathogenic microorganisms. Barrier dysfunction promotes chronic inflammation, which can drive the pathogenesis of inflammatory bowel disease (IBD) and colorectal cancer (CRC). Although the Signal Transducer and Activator of Transcription-3 (STAT3) is overexpressed in both intestinal epithelial cells and immune cells in IBD patients, the role of the interleukin (IL)-6 family of cytokines through the shared IL-6ST/gp130 receptor and its associated STAT3 signalling in intestinal barrier integrity is unclear. We therefore investigated the role of STAT3 in retaining epithelial barrier integrity using dextran sulfate sodium (DSS)-induced colitis in two genetically modified mouse models, to either reduce STAT1/3 activation in response to IL-6 family cytokines with a truncated gp130∆STAT allele (GP130∆STAT/+), or by inducing short hairpin-mediated knockdown of Stat3 (shStat3). Here, we show that mice with reduced STAT3 activity are highly susceptible to DSS-induced colitis. Mechanistically, the IL-6/gp130/STAT3 signalling cascade orchestrates intestinal barrier function by modulating cytokine secretion and promoting epithelial integrity to maintain a defence against bacteria. Our study also identifies a crucial role of STAT3 in controlling intestinal permeability through tight junction proteins. Thus, therapeutically targeting the IL-6/gp130/STAT3 signalling axis to promote barrier function may serve as a treatment strategy for IBD patients.

The Role of gp130 Cytokines in Tuberculosis.

Protective immune responses to Mycobacterium tuberculosis (Mtb) infection substantially depend on a delicate balance within cytokine networks. Thus, immunosuppressive therapy by cytokine blockers, as successfully used in the management of various chronic inflammatory diseases, is often connected with an increased risk for tuberculosis (TB) reactivation. Hence, identification of alternative therapeutics which allow the treatment of inflammatory diseases without compromising anti-mycobacterial immunity remains an important issue. On the other hand, in the context of novel therapeutic approaches for the management of TB, host-directed adjunct therapies, which combine administration of antibiotics with immunomodulatory drugs, play an increasingly important role, particularly to reduce the duration of treatment. In both respects, cytokines/cytokine receptors related to the common receptor subunit gp130 may serve as promising target candidates. Within the gp130 cytokine family, interleukin (IL)-6, IL-11 and IL-27 are most explored in the context of TB. This review summarizes the differential roles of these cytokines in protection and immunopathology during Mtb infection and discusses potential therapeutic implementations with respect to the aforementioned approaches.

Gp130 Cytokines Activate Novel Signaling Pathways and Alter Bone Dissemination in ER+ Breast Cancer Cells.

Breast cancer cells frequently home to the bone marrow, where they encounter signals that promote survival and quiescence or stimulate their proliferation. The interleukin-6 (IL-6) cytokines signal through the co-receptor glycoprotein130 (gp130) and are abundantly secreted within the bone microenvironment. Breast cancer cell expression of leukemia inhibitory factor (LIF) receptor (LIFR)/STAT3 signaling promotes tumor dormancy in the bone, but it is unclear which, if any of the cytokines that signal through LIFR, including LIF, oncostatin M (OSM), and ciliary neurotrophic factor (CNTF), promote tumor dormancy and which signaling pathways are induced. We first confirmed that LIF, OSM, and CNTF and their receptor components were expressed across a panel of breast cancer cell lines, although expression was lower in estrogen receptor-negative (ER- ) bone metastatic clones compared with parental cell lines. In estrogen receptor-positive (ER+ ) cells, OSM robustly stimulated phosphorylation of known gp130 signaling targets STAT3, ERK, and AKT, while CNTF activated STAT3 signaling. In ER- breast cancer cells, OSM alone stimulated AKT and ERK signaling. Overexpression of OSM, but not CNTF, reduced dormancy gene expression and increased ER+ breast cancer bone dissemination. Reverse-phase protein array revealed distinct and overlapping pathways stimulated by OSM, LIF, and CNTF with known roles in breast cancer progression and metastasis. In breast cancer patients, downregulation of the cytokines or receptors was associated with reduced relapse-free survival, but OSM was significantly elevated in patients with invasive disease and distant metastasis. Together these data indicate that the gp130 cytokines induce multiple signaling cascades in breast cancer cells, with a potential pro-tumorigenic role for OSM and pro-dormancy role for CNTF. © 2021 American Society for Bone and Mineral Research (ASBMR).

Correction: Multimerization strategies for efficient production and purification of highly active synthetic cytokine receptor ligands

[This corrects the article DOI: 10.1371/journal.pone.0230804.].

Abstract 2644: Oncostatin M in pancreatic cancer tumor microenvironment

Abstract The Pancreatic Ductal Adenocarcinoma (PDAC) tumor microenvironment (TME) is comprised of numerous cell types. Among those, cancer associated fibroblasts (CAFs) play roles in tumor development, drug resistance, fibrosis and inflammation. GP130 cytokines, including Interleukin-6 (IL-6) and Leukemia Inhibitory Factor in the TME are implicated in pancreatic cancer progression and drug resistance, but less is known of the other cytokines in this family. Oncostatin M (OSM) enhances tumorigenicity, regulates tissue remodeling, and activates epithelial-to-mesenchymal transition in cancer; however, the functions of OSM in the pancreatic cancer TME and relevant phenotypes in PDAC patients have not been fully elucidated. Staining of murine tumor tissue revealed staining of OSM in tumor cells, and its receptor, OSMR, in tumor cells and fibroblasts. To model the effects of OSM in the TME, we used a spheroid culture system with patient-derived tumor cells (Pa03C cells) and patient-derived pancreatic cancer associated fibroblasts (CAF3 and CAF19) treated with rhOSM. In vitro, OSM promoted activation and proliferation of CAF monocultures, but had no effect on tumor cells. In co-cultures, OSM caused clustering of CAFs, resulting in a denser and more fibrotic spheroid with a network of CAFs clustered tightly around tumor cells. There was no effect of OSM on tumor cells in monoculture, suggesting the effects of OSM are mediated on and through fibroblasts. To study OSM in human PDAC, we used TCGA for expression and correlative gene analysis. OSM expression in tumors did not correlate with survival. In contrast, high expression of OSMR correlated with decreased patient survival (p=0.051). This effect was sex-specific–the top quartile of OSMR expressing tumors associated with median overall survival (OS) of 600 days, while the bottom three quartiles showed OS of 1100 days (p=0.0047). There was no correlation with OSMR expression and survival in female patients. Tumor OSM and OSMR expression were not different between the sexes, however. For OSM, 504 genes correlated positively with r&amp;gt;0.03. For OSMR, 5962 genes correlated with |r|0.3, with OSM identified as an upstream regulator (Z-score 5.770). The top upstream regulators identified in common between the OSM and OSMR correlated genes were lipopolysaccharide (Z-scores 8.408 and 8.556 for OSM and OSMR respectively), TGFB1 (7.562 and 8.799), and TNF (7.397 and 6.813), linking inflammation to fibrosis in the TME. Taken together with data from our functional studies, these data suggest that OSM and OSMR modulate the PDAC tumor microenvironment and disease outcomes in PDAC. More functional investigation is warranted for this important pathway. Citation Format: Daenique H. Jengelley, Melissa L. Fishel, Michael Ostrowski, Teresa A. Zimmers. Oncostatin M in pancreatic cancer tumor microenvironment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2644.

A variant in IL6ST with a selective IL-11 signaling defect in human and mouse

The GP130 cytokine receptor subunit encoded by IL6ST is the shared receptor for ten cytokines of the IL-6 family. We describe a homozygous non-synonymous variant in IL6ST (p.R281Q) in a patient with craniosynostosis and retained deciduous teeth. We characterize the impact of the variant on cytokine signaling in vitro using transfected cell lines as well as primary patient-derived cells and support these findings using a mouse model with the corresponding genome-edited variant Il6st p.R279Q. We show that human GP130 p.R281Q is associated with selective loss of IL-11 signaling without affecting IL-6, IL-27, OSM, LIF, CT1, CLC, and CNTF signaling. In mice Il6st p.R279Q lowers litter size and causes facial synostosis and teeth abnormalities. The effect on IL-11 signaling caused by the GP130 variant shows incomplete penetrance but phenocopies aspects of IL11RA deficiency in humans and mice. Our data show that a genetic variant in a pleiotropic cytokine receptor can have remarkably selective defects.

RELMα is Induced in Airway Epithelial Cells by Oncostatin M Without Requirement of STAT6 or IL-6 in Mouse Lungs In Vivo.

Resistin-like molecule alpha (RELMα) and YM-1 are secreted proteins implicated in murine models of alternatively activated macrophage (AA/M2) accumulation and Th2-skewed inflammation. Since the gp130 cytokine Oncostatin M (OSM) induces a Th2-like cytokine and AA/M2 skewed inflammation in mouse lung, we here investigated regulation of RELMα and YM-1. Transient pulmonary overexpression of OSM by Adenovirus vector (AdOSM) markedly induced RELMα and YM-1 protein expression in total lung. In situ hybridization showed that RELMα mRNA was highly induced in airway epithelial cells (AEC) and was co-expressed with CD68 mRNA in some but not all CD68+ cells in parenchyma. IL-6 overexpression (a comparator gp130 cytokine) induced RELMα, but at significantly lower levels. IL-6 (assessing IL-6−/− mice) was not required, nor was STAT6 (IL-4/13 canonical signalling) for AdOSM-induction of RELMα in AEC. AEC responded directly to OSM in vitro as assessed by pSTAT3 activation. RELMα-deficient mice showed similar inflammatory cell infiltration and cytokine responses to wt in response to AdOSM, but showed less accumulation of CD206+ AA/M2 macrophages, reduced induction of extracellular matrix gene mRNAs for COL1A1, COL3A1, MMP13, and TIMP1, and reduced parenchymal alpha smooth muscle actin. Thus, RELMα is regulated by OSM in AEC and contributes to extracellular matrix remodelling in mouse lung.

Multimerization strategies for efficient production and purification of highly active synthetic cytokine receptor ligands.

Cytokine signaling is transmitted by cell surface receptors which act as natural biological switches to control cellular functions such as immune reactions. Recently, we have designed synthetic cytokine receptors (SyCyRs) consisting of green fluorescent protein (GFP)- and mCherry-nanobodies fused to the transmembrane and intracellular domains of cytokine receptors. Following stimulation with homo- and heterodimeric GFP-mCherry fusion proteins, the resulting receptors phenocopied signaling induced by physiologically occurring cytokines. GFP and mCherry fusion proteins were produced in E. coli or CHO-K1 cells, but the overall yield and stability was low. Therefore, we applied two alternative multimerization strategies and achieved immunoglobulin Fc-mediated dimeric and coiled-coil GCN4pII-mediated trimeric assemblies. GFP- and/or mCherry-Fc homodimers activated synthetic gp130 cytokine receptors, which naturally respond to Interleukin 6 family cytokines. Activation of these synthetic gp130 receptors resulted in STAT3 and ERK phosphorylation and subsequent proliferation of Ba/F3-gp130 cells. Half-maximal effective concentrations (EC50) of 8.1 ng/ml and 0.64 ng/ml were determined for dimeric GFP-Fc and mCherry-Fc, respectively. This is well within the expected EC50 range of the native cytokines. Moreover, we generated tetrameric and hexameric GFP-mCherry-Fc fusion proteins, which were also biologically active. This highlighted the importance of close juxtaposition of two cytokine receptors for efficient receptor activation. Finally, we used a trimeric GCN4pII motif to generate homo-trimeric GFP and mCherry complexes. These synthetic cytokines showed improved EC50 values (GFP3: 0.58 ng/ml; mCherrry3: 0.37 ng/ml), over dimeric Fc fused variants. In conclusion, we successfully generated highly effective and stable multimeric synthetic cytokine receptor ligands for activation of synthetic cytokine receptors.

SOCS3 is a suppressor of γc cytokine signaling and constrains generation of murine Foxp3+ regulatory T cells

SOCS3 is a cytosolic inhibitor of cytokine signaling that suppresses the activation of cytokine receptor-associated JAK kinases. Mechanistically, SOCS3 is recruited to a site in the cytokine receptors known as the SOCS3-interaction motif, and then binds JAK molecules to inhibit their kinase activity. The SOCS3-interaction motif is found in receptors of the gp130 cytokine family but mostly absent from other cytokine receptors, including γc. Thus, SOCS3 has been considered a selective suppressor of gp130 family cytokines, but not γc cytokines. Considering that γc signaling induces SOCS3 expression in T cells, here we revisited the role of SOCS3 on γc signaling. Using SOCS3 transgenic mice, we found that increased abundance of SOCS3 not only suppressed signaling of the gp130 family cytokine IL-6, but also signaling of the γc family cytokine IL-7. Consequently, SOCS3 transgenic mice were impaired in IL-7-dependent T cell development in the thymus and the homeostasis of mature T cells in peripheral tissues. Moreover, enforced SOCS3 expression interfered with the generation of Foxp3+ regulatory T cells that requires signaling by the γc family cytokine IL-2. Collectively, we report an underappreciated role for SOCS3 in suppressing γc cytokine signaling, effectively expanding its scope of target cytokines in T cell immunity.

GP130 Cytokines in Breast Cancer and Bone

Breast cancer cells have a high predilection for skeletal homing, where they may either induce osteolytic bone destruction or enter a latency period in which they remain quiescent. Breast cancer cells produce and encounter autocrine and paracrine cytokine signals in the bone microenvironment, which can influence their behavior in multiple ways. For example, these signals can promote the survival and dormancy of bone-disseminated cancer cells or stimulate proliferation. The interleukin-6 (IL-6) cytokine family, defined by its use of the glycoprotein 130 (gp130) co-receptor, includes interleukin-11 (IL-11), leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF), and cardiotrophin-1 (CT-1), among others. These cytokines are known to have overlapping pleiotropic functions in different cell types and are important for cross-talk between bone-resident cells. IL-6 cytokines have also been implicated in the progression and metastasis of breast, prostate, lung, and cervical cancer, highlighting the importance of these cytokines in the tumor–bone microenvironment. This review will describe the role of these cytokines in skeletal remodeling and cancer progression both within and outside of the bone microenvironment.

Oncostatin M in the Regulation of Connective Tissue Cells and Macrophages in Pulmonary Disease.

Oncostatin M (OSM), as one of the gp130/IL-6 family of cytokines, interacts with receptor complexes that include the gp130 signaling molecule and OSM receptor β OSMRβ chain subunits. OSMRβ chains are expressed relatively highly across a broad array of connective tissue (CT) cells of the lung, such as fibroblasts, smooth muscle cells, and epithelial cells, thus enabling robust responses to OSM, compared to other gp130 cytokines, in the regulation of extracellular matrix (ECM) remodeling and inflammation. OSMRβ chain expression in lung monocyte/macrophage populations is low, whereas other receptor subunits, such as that for IL-6, are present, enabling responses to IL-6. OSM is produced by macrophages and neutrophils, but not CT cells, indicating a dichotomy of OSM roles in macrophage verses CT cells in lung inflammatory disease. ECM remodeling and inflammation are components of a number of chronic lung diseases that show elevated levels of OSM. OSM-induced products of CT cells, such as MCP-1, IL-6, and PGE2 can modulate macrophage function, including the expression of OSM itself, indicating feedback loops that characterize Macrophage and CT cell interaction.