Search

Cachexia is a wasting syndrome that manifests in more than half of all cancer patients. Cancer-associated cachexia negatively influences the survival of patients and their quality of life. It is characterized by a rapid loss of adipose and skeletal muscle tissues, which is partly mediated by inflammatory cytokines. Here, we explored the crucial roles of interleukin-6 (IL-6) family cytokines, including IL-6, leukemia inhibitory factor, and oncostatin M, in the development of cancer cachexia. These cytokines have been shown to exacerbate cachexia by promoting the wasting of adipose and muscle tissues, activating mechanisms that enhance lipolysis and proteolysis. Overlapping effects of the IL-6 family cytokines depend on janus kinase/signal transducer and activator of transcription 3 signaling. We argue that the blockade of these cytokine pathways individually may fail due to redundancy and future therapeutic approaches should target common downstream elements to yield effective clinical outcomes., (© 2024 The Author(s). The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Background: Oncostatin M (OSM) is a secreted cytokine of the interleukin (IL)-6 family that induces biological effects by activating functional receptor complexes of the common signal transducing component glycoprotein 130 (gp130) and OSM receptor β (OSMR) or leukaemia inhibitory factor receptor (LIFR), which are mainly involved in chronic inflammatory and cardiovascular diseases. The effect and underlying mechanism of OSM/OSMR/LIFR on the development of cardiac hypertrophy remains unclear., Methods and Results: OSMR-knockout (OSMR-KO) mice were subjected to aortic banding (AB) surgery to establish a model of pressure overload-induced cardiac hypertrophy. Echocardiographic, histological, biochemical and immunological analyses of the myocardium and the adoptive transfer of bone marrow-derived macrophages (BMDMs) were conducted for in vivo studies. BMDMs were isolated and stimulated with lipopolysaccharide (LPS) for the in vitro study. OSMR deficiency aggravated cardiac hypertrophy, fibrotic remodelling and cardiac dysfunction after AB surgery in mice. Mechanistically, the loss of OSMR activated OSM/LIFR/STAT3 signalling and promoted a proresolving macrophage phenotype that exacerbated inflammation and impaired cardiac repair during remodelling. In addition, adoptive transfer of OSMR-KO BMDMs to WT mice after AB surgery resulted in a consistent hypertrophic phenotype. Moreover, knockdown of LIFR in myocardial tissue with Ad-shLIFR ameliorated the effects of OSMR deletion on the phenotype and STAT3 activation., Conclusions: OSMR deficiency aggravated pressure overload-induced cardiac hypertrophy by modulating macrophages and OSM/LIFR/STAT3 signalling, which provided evidence that OSMR might be an attractive target for treating pathological cardiac hypertrophy and heart failure., (© 2023. The Author(s).)

Although recent evidence indicates that gp130 cytokines, Oncostatin M (OSM) and IL-6 are involved in alternative programming of macrophages, their role in lung fibrogenesis is poorly understood. Here, we investigated the effect of transient adenoviral overexpression of OSM or IL-6 in mice during bleomycin-induced lung fibrosis. Lung fibrosis and M2-like macrophage accumulation were assessed by immunohistochemistry, western blotting, gene expression and flow cytometry. Ex-vivo isolated alveolar and bone marrow-derived macrophages were examined for M2-like programming and signalling. Airway physiology measurements at day 21 demonstrated that overexpression of OSM or IL-6 exacerbated bleomycin-induced lung elastance, consistent with histopathological assessment of extracellular matrix and myofibroblast accumulation. Flow cytometry analysis at day 7 showed increased numbers of M2-like macrophages in lungs of mice exposed to bleomycin and OSM or IL-6. These macrophages expressed the IL-6Rα, but were deficient for OSMRβ, suggesting that IL-6, but not OSM, may directly induce alternative macrophage activation. In conclusion, the gp130 cytokines IL-6 and OSM contribute to the accumulation of profibrotic macrophages and enhancement of bleomycin-induced lung fibrosis. This study suggests that therapeutic strategies targeting these cytokines or their receptors may be beneficial to prevent the accumulation of M2-like macrophages and the progression of fibrotic lung disease.

The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor that mediates the toxicity of dioxins, polycyclic aromatic hydrocarbons and related environmental pollutants. Besides drug metabolism, several studies have provided evidence that the AHR and its downstream targets trigger important developmental, physiological and pathophysiological processes. However, in contrast to the molecular mechanisms of AHR-dependent signaling pathways, the transcriptional regulation of the AHR gene itself is as yet only marginally understood. We found that the pleiotropic interleukin (IL)-6-type cytokine oncostatin M (OSM) is an inducer of AHR mRNA and protein expression in human HepG2 hepatocarcinoma cells. Analyses of the human AHR promoter revealed the existence of a putative signal transducer and activator of transcription (STAT)-binding element 5'-upstream of the transcription start site. By means of site-directed mutagenesis, inhibitor experiments and electrophoretic mobility shift assays, we demonstrated that this STAT motif is recognized by STAT3 to regulate basal and cytokine-inducible AHR expression in HepG2 cells. The identification of the AHR as a downstream target of IL-6-type cytokine-stimulated STAT3 signaling may contribute to a better understanding of the multiple facets of AHR during development, physiology and disease., (© 2013 FEBS.)

Unlabelled: Chronic inflammation has been proposed as an etiological and progression factor in prostate cancer. In this study, we used a dissociated prostate tissue recombination system to interrogate the role of interleukin 6 (IL6) and the related cytokine oncostatin-M (OSM) in the initiation and progression of prostate cancer. We identified that prostatic intraepithelial neoplasia (PIN) lesions induced by PTEN loss of function (PTEN(LOF)) progress to invasive adenocarcinoma following paracrine expression of either cytokine. Increased expression of OSM was also able to drive progression of benign human epithelium when combined with constitutively activated AKT. Malignant progression in the mouse was associated with invasion into the surrounding mesenchyme and increased activation of STAT3 in PTEN(LOF) grafts expressing IL6 or OSM. Collectively, our work indicates that pro-inflammatory cytokines such as IL6 or OSM could activate pathways associated with prostate cancer progression and synergize with cell-autonomous oncogenic events to promote aggressive malignancy., Implications: Increased expression of IL6 or OSM synergizes with loss of PTEN to promote invasive prostate cancer. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/early/2013/09/02/1541-7786.MCR-13-0238/F1.large.jpg.

Inducible BALT (iBALT) is associated with immune responses to respiratory infections as well as with local pathology derived from chronic inflammatory lung diseases. In this study, we assessed the role of oncostatin M (OSM) in B cell activation and iBALT formation in mouse lungs. We found that C57BL/6 mice responded to an endotracheally administered adenovirus vector expressing mouse OSM, with marked iBALT formation, increased cytokine (IL-4, IL-5, IL-6, IL-10, TNF-α, and IL-12), and chemokine (CXCL13, CCL20, CCL21, eotaxin-2, KC, and MCP-1) production as well as inflammatory cell accumulation in the airways. B cells, T cells, and dendritic cells were also recruited to the lung, where many displayed an activated phenotype. Mice treated with control adenovirus vector (Addl70) were not affected. Interestingly, IL-6 was required for inflammatory responses in the airways and for the expression of most cytokines and chemokines. However, iBALT formation and lymphocyte recruitment to the lung tissue occurred independently of IL-6 and STAT6 as assessed in gene-deficient mice. Collectively, these results support the ability of OSM to induce B cell activation and iBALT formation independently of IL-6 and highlight a role for IL-6 downstream of OSM in the induction of pulmonary inflammation.

Objective: To investigate whether signaling through Toll-like receptor-2 (TLR-2) can affect the expression of some cytokines in human gingival fibroblasts., Methods: The gingival fibroblasts were isolated and cultured in vivo, divided into blank control group, lipopolysaccharide (LPS) from Porphyromonas gingivalis (Pg) group and Escherichia coli (Ec) group. mRNA expression levels were measured by real-time polymerase chain reaction (PCR). The protein expression levels were detected by the enzyme linked immunosorbent assay (ELISA). The data was statistically analyzed by SPSS16.0 software package., Results: LPS from Pg could stimulate the expression of interleukin (IL)-6 and leukemia inhibitory factor (LIF) mRNA and protein, which reached the peak (5.87 ± 0.83) at 10 h, and the expression level increased with the increase of the Pg concentration. IL-11 or oncostatin-M (OSM) mRNA expression was not affected by LPS. After treated with Pg for 48 h, the protein expression of IL-6 and LIF was up-regulated, (962 ± 57) ng/L and (47 ± 18) ng/L respectively., Conclusions: Signaling through TLR-2 controls the expression of cytokines of IL-6 family in human gingival fibroblasts.

This study was aimed to investigate the hematopoietic growth factors expressed in human aorta-gonad-mesonephros (AGM)-derived stromal cells in vitro in order to provide the basic data for elucidating the role of AGM -derived-stromal cells in embryo-hematopoiesis and its hematopoietic suppoitive effect. RT-PCR was used to analyze the expression of IL-6, SCF, Flt3-L, oncostatin M (OSM), IL-3, TPO, M-CSF and LIF in human aorta-gonad-mesonephros-derived stromal cells (hAGMS1-S5) at mRNA level. IL-6, SCF and Flt3-L levels were detected in the supernatant of hAGMS1-S5 stromal cells by ELISA assay. Umbilical cord blood CD34(+) cells were cocultured with hAGMS1-S5 feeder cells, and hematopoietic cells were collected at day 14 for colony analysis in methylcellulose semisolid medium. The results showed that human aorta-gonad-mesonephros-derived stromal cells S1-S5 expressed IL-6, SCF, Flt3-L and OSM mRNA, but did not express IL-3, TPO, M-CSF and LIF mRNA. In the supernatant of hAGMS1-S5 cells, IL-6, SCF and Flt3-L could be detected by ELISA assay at different levels, while there was no significant difference between groups of hAGMS1-S5 (P > 0.05). When cocultured with umbilical cord blood CD34(+) cells, hAGMS1-S5 could support the expansion of CFU-GM, BFU-E, and CFU-Mix. The supportive effects of hAGM S1-S5 were significantly different (P < 0.05), hAGM S3 and S4 were better than hAGM S1, S2, and S5. It is concluded that detection of hematopoietic growth factors expressed in human aorta-gonad-mesonephros-derived stromal cells provided a solid foundation to elucidate the mechanism of hematopoiesis and the hematopoietic supportive effect of these stromal cells.