Growth differentiation factor 15 (GDF15) promotes human rhinovirus infection and inflammation
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE100625 | GEO | 2017/10/08
SECONDARY ACCESSION(S): PRJNA392313
REPOSITORIES: GEO
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Project description:Growth differentiating factor (GDF)15 is a TGFβ superfamily cytokine and a reported biomarker of heart failure. Myocardial expression of GDF15 is increased in heart failure. Yet, the mechanisms that control synthesis and release of GDF15 as well as the autocrine/paracrine functions of GDF15 on fibroblast function is lacking. Thus, the aim of this study was to investigate signaling pathways and functions of GDF15 in cardiac fibroblasts. Cardiac fibroblasts and cardiac myocytes were isolated from adult C57/BL6 mice, maintained in primary culture and stimulated with recombinant (r)GDF15 or recombinant (r)CCN2. Short-term stimulation (30 minutes) of cardiac fibroblasts demonstrated a GDF15-induced activation of several intracellular signaling pathways including a concentration-dependent increase of phospho-Smad3(Ser423/425) (p<0.05, n=3), phospho-AKT(Ser473) (p<0.05, n=3) and phospho-IκBα(Ser32/36) (p<0.05, n=3) levels. However, rGDF15 did not phosphorylate Smad3(Ser423/425) or IκBα(Ser32/36) in cardiac myocyte. Cardiac fibroblasts exposed to rGDF15 for 48 hours displayed differentiation towards myofibroblasts reflected by increased levels of the differentiation marker α-smooth muscle actin (SMA) similar to cardiac fibroblasts stimulated with TGFβ. The effect of GDF15 on α-SMA was dose-dependent ranging from 500 nM - 20 nM rGDF15 (p<0.05, n=3). Differentiation towards a myofibroblast phenotype in the presence of GDF15 was also supported by higher matrix metalloproteinase (MMP) enzyme activity in the cell culture medium (6±1 fold increase, n=3, p<0.05) and increased expression and release of MMP-3, 9 and 13. Immunoreactive GDF15 was predominantly found in cardiac myocytes. Recombinant CCN2 substantially induced GDF15 expression in cardiac myocytes, but not in cardiac fibroblasts. In conclusion, our data demonstrate that GDF15 is a paracrine factor in myocardial tissue and specifically regulated by CCN2 in cardiac myocytes. GDF15 has similar effects as TGFβ on fibroblasts by activation of intracellular signaling pathways and differentiation to a myofibroblasts phenotype.
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Project description:To systematically profile the GDF15-regulated genes in hepatoma cells and to elucidate the possible role of GDF15 on biological processes, high-density oligonucleotide microarrays were hybridized with samples prepared from GDF15- or PBS-treated Huh7.5.1 cells. We found that a total of 894 genes were differentially expressed in response to GDF15 treatment based on the 2-fold cut-off range, and a majority (828 genes, about 92.6%) of the genes is up-regulated. According to the descriptions outlined by the Gene Ontology Biological Process, the differentially expressed genes were found to belong to a variety of functional categories. Two samples were included in the experiment. They are Huh7.5.1 cells treated with PBS, and Huh7.5.1 cells treated with recombinant human growth and differentiation factor 15. Twenty four hours post treatment, the total RNA was isolated from the cells. The microarray hybridization and analysis were performed by CapitalBio Corporation using the 22K Human Genome Array. Two-channel hybridizations microarray assay was performed.
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Project description:Tumor-associated macrophages (TAMs) are known to be involved in progression, angiogenesis and motility of various cancers. We have previously reported the association between increased number of infiltrating TAMs with tumor progression and poor prognosis in esophageal squamous cell carcinomas (ESCCs). To study roles of TAMs in ESCC, we first exposed peripheral blood monocytes (PBMo) derived macrophages from healthy volunteers to conditioned media of TE series human ESCC cell line (TECM) and confirmed the induction of expression of M2 macrophage marker, CD204, and protumorigenic factors, interleukin (IL)-10, VEGFA and MMPs. Next, we compared gene expression profile between PBMo-derived macrophages and PBMo-derived macrophages stimulated with TECM by cDNA microarray. Based on the result, we focused on growth differentiation factor 15 (GDF15) among highly expressed genes including IL-6, IL-8 and CXCL1. Immunohistochemical study on 70 cases of surgically resected ESCCs revealed that GDF15 was detected not only in macrophages but also in cancer cells. High expression of GDF15 in ESCCs was significantly correlated with more malignant phenotypes including lymph and blood vessel invasion, lymph node metastasis as well as clinical stages. Patients with high expression of GDF15 showed poor disease-free survival (p = 0.011) and overall survival (p = 0.041). Furthermore, we found that recombinant human GDF15 promote cell proliferation and phosphorylation of both Akt and Erk1/2 in ESCC cell lines in vitro. These results indicate that GDF15 is secreted by both TAMs and cancer cells in tumor microenvironment and is associated with aberrant growth and poor prognosis of human ESCC. We exposed PBMo-derived macrophages from healthy volunteers to TECM and observed their acquisition of TAM-like characters in this study. We further investigated specific cancer-associated gene expression profile in TECM induced TAM-like macrophages by cDNA microarray analysis.
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Project description:Heart failure and associated cachexia is an unresolved and important problem. We report a new model of severe heart failure that consistently results in cachexia. Mice lacking the integrated stress response (ISR) induced eIF2α phosphatase, PPP1R15A, exhibit a dilated cardiomyopathy and severe weight loss following irradiation, whilst wildtype mice are unaffected. This is associated with increased expression of Gdf15 in the heart and increased levels of GDF15 in the circulation. We provide evidence that blockade of GDF15 activity prevents cachexia and slows the progression of heart failure. Our data suggests that cardiac stress mediates a GDF15 dependent pathway that drives weight loss and worsens cardiac function. We show relevance of GDF15 to lean mass and protein intake with patients with heart failure. Blockade of GDF15 could constitute a novel therapeutic option to limit cardiac cachexia and improve clinical outcomes in patients with severe systolic heart failure.
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Project description:Growth Differentiation Factor 15 (GDF15) is a divergent member of the TGF-β superfamily, and its expression increases under various stress conditions, including inflammation, hyperoxia, and senescence. GDF15 expression is increased in neonatal murine BPD models, and GDF15 loss exacerbates oxidative stress and decreases viability in vitro in pulmonary epithelial and endothelial cells. Our overall hypothesis is that the loss of GDF15 will exacerbate hyperoxic lung injury in the neonatal lung in vivo. We exposed neonatal Gdf15-/- mice and wild-type (WT) controls on a similar background to room air or hyperoxia (95% O2) for 5 days after birth. The mice were euthanized on PND 21. Gdf15 -/- mice had higher mortality and lower body weight than WT mice after exposure to hyperoxia. Upon exposure to hyperoxia, female mice had higher alveolar simplification in the Gdf15-/- group than the female WT group. Gdf15-/- and WT mice showed no difference in the degree of the arrest in angiogenesis upon exposure to hyperoxia. Gdf15-/- mice showed lower macrophage count in the lungs compared to WT mice. Our results suggest that Gdf15 deficiency decreases the tolerance to hyperoxic lung injury with evidence of sex-specific differences.
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Project description:Tumor-associated macrophages (TAMs) are known to be involved in progression, angiogenesis and motility of various cancers. We have previously reported the association between increased number of infiltrating TAMs with tumor progression and poor prognosis in esophageal squamous cell carcinomas (ESCCs). To study roles of TAMs in ESCC, we first exposed peripheral blood monocytes (PBMo) derived macrophages from healthy volunteers to conditioned media of TE series human ESCC cell line (TECM) and confirmed the induction of expression of M2 macrophage marker, CD204, and protumorigenic factors, interleukin (IL)-10, VEGFA and MMPs. Next, we compared gene expression profile between PBMo-derived macrophages and PBMo-derived macrophages stimulated with TECM by cDNA microarray. Based on the result, we focused on growth differentiation factor 15 (GDF15) among highly expressed genes including IL-6, IL-8 and CXCL1. Immunohistochemical study on 70 cases of surgically resected ESCCs revealed that GDF15 was detected not only in macrophages but also in cancer cells. High expression of GDF15 in ESCCs was significantly correlated with more malignant phenotypes including lymph and blood vessel invasion, lymph node metastasis as well as clinical stages. Patients with high expression of GDF15 showed poor disease-free survival (p = 0.011) and overall survival (p = 0.041). Furthermore, we found that recombinant human GDF15 promote cell proliferation and phosphorylation of both Akt and Erk1/2 in ESCC cell lines in vitro. These results indicate that GDF15 is secreted by both TAMs and cancer cells in tumor microenvironment and is associated with aberrant growth and poor prognosis of human ESCC.
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