Transforming Growth Factor-β1: A Novel Cause of Resistance to Bronchodilators in Asthma?
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ABSTRACT:
SUBMITTER: Wortley MA
PROVIDER: S-EPMC6670036 | biostudies-literature |
REPOSITORIES: biostudies-literature
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2011-11-22 | E-GEOD-28122 | biostudies-arrayexpress
Project description:Transforming growth factor-β1 (TGF-β1) is inextricably linked to regulatory T cell (Treg) biology. However, precisely untangling the role for TGF-β1 in Treg differentiation and function is complicated by the pleiotropic and context-dependent activity of this cytokine and the multifaceted biology of Tregs. Among CD4+ T cells, Tregs are the major producers of latent TGF-β1 and are uniquely able to activate this cytokine via expression of cell surface docking receptor glycoprotein A repetitions predominant (GARP) and αv integrins. Although a preponderance of evidence indicates no essential roles for Treg-derived TGF-β1 in Treg immunosuppression, TGF-β1 signaling is crucial for Treg development in the thymus and periphery. Furthermore, active TGF-β1 instructs the differentiation of other T cell subsets, including TH17 cells. Here, we will review TGF-β1 signaling in Treg development and function and discuss knowledge gaps, future research, and the TGF-β1/Treg axis in the context of cancer immunotherapy and fibrosis.
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Project description:BackgroundIntrinsic and extrinsic factors in the tumour microenvironment (TME) contribute to therapeutic resistance. Here we demonstrate that transforming growth factor (TGF)-β1 produced in the TME increased drug resistance of neuroblastoma (NB) cells.MethodsHuman NB cell lines were tested in vitro for their sensitivity to Doxorubicin (DOX) and Etoposide (ETOP) in the presence of tumour-associated macrophages (TAM) and mesenchymal stromal cells/cancer-associated fibroblasts (MSC/CAF). These experiments were validated in xenotransplanted and primary tumour samples.ResultsDrug resistance was associated with an increased expression of efflux transporter and anti-apoptotic proteins. Upregulation was dependent on activation of nuclear factor (NF)-κB by TGF-β-activated kinase (TAK1) and SMAD2. Resistance was reversed upon pharmacologic and genetic inhibitions of NF-κB, and TAK1/SMAD2. Interleukin-6, leukaemia inhibitory factor and oncostatin M were upregulated by this TGF-β/TAK1/NF-κB/SMAD2 signalling pathway contributing to drug resistance via an autocrine loop activating STAT3. An analysis of xenotransplanted NB tumours revealed an increased presence of phospho (p)-NF-κB in tumours co-injected with MSC/CAF and TAM, and these tumours failed to respond to Etoposide but responded if treated with a TGF-βR1/ALK5 inhibitor. Nuclear p-NF-κB was increased in patient-derived tumours rich in TME cells.ConclusionsThe data provides a novel insight into a targetable mechanism of environment-mediated drug resistance.
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2011-11-22 | GSE28122 | GEO