Mesenchymal stromal cell plasticity and the tumor microenvironment

2017 ◽  
Vol 1 (5) ◽  
pp. 487-492
Author(s):  
Hee Joon Bae ◽  
Shutong Liu ◽  
Ping Jin ◽  
David Stroncek
Keyword(s):  
Tumor Microenvironment ◽  
Transforming Growth Factor ◽  
Critical Role ◽  
Tumor Infiltrating Lymphocytes ◽  
Transforming Growth Factor Β ◽  
Interferon Γ ◽  
Tnf Α ◽  
Ifn Γ ◽  
Factor Α ◽  
Infiltrating Lymphocytes

Mesenchymal stem cells or mesenchymal stromal cells (MSCs) are a multipotent, heterogeneous population of cells that play a critical role in wound healing and tissue regeneration. MSCs, found in the tumor microenvironment, support tumor growth through the production of angiogenic factors, growth factors and extracellular matrix proteins. They also have immunomodulatory properties, and since they produce indoleamine 2,3-dioxygenase (IDO), prostaglandin E2 (PGE2) and transforming growth factor β (TGF-β), they have been thought to have primarily immunosuppressive effects. However, their role in the tumor microenvironment is complex and demonstrates plasticity depending on location, stimulatory factors and environment. The presence of melanoma-activated tumor-infiltrating lymphocytes (TILs) has been shown to produce pro-inflammatory changes with TH1 (type 1T helper)-like phenotype in MSCs via activated-TIL released cytokines such as interferon γ (IFN-γ), tumor necrosis factor α (TNF-α) and interleukin-1α (IL-1α), while simultaneously producing factors, such as IDO1, which have been traditionally associated with immunosuppression. Similarly, the combination of IFN-γ and TNF-α polarizes MSCs to a primarily TH1-like phenotype with the expression of immunosuppressive factors. Ultimately, further studies are encouraged and needed for a greater understanding of the role of MSCs in the tumor microenvironment and to improve cancer immunotherapy.

Effects of transforming growth factor β, tumor necrosis factor α and interferon γ on pancreatic islet β-cell responsiveness to transforming growth factor α

1996 ◽  
Vol 16 (5) ◽  
pp. 415-423 ◽  
Author(s):  
Åke Sjöholm
Keyword(s):  
Insulin Secretion ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Insulin Content ◽  
Β Cell ◽  
Transforming Growth Factor Α ◽  
Tnf Α ◽  
Ifn Γ ◽  
Factor Α

The insulin-producing pancreatic islet β-cell, characterized by low proliferative potential, is normally not responsive to the polypeptide epidermal growth factor (EGF) or its homolog transforming growth factor α (TGF-α). Since EGF receptors in other tissues can be up-regulated by other growth factors and by cytokines, we have in this paper investigated whether such a β-cell responsiveness to TGF-α, or EGF, can be conferred by co-culture with interferon γ (IFN-γ), tumor necrosis factor α (TNF-α) or transforming growth factor β (TGF-β) in various combinations. To this end, fetal rat pancreatic islets enriched in β-cells were isolated and cultured for 3 days with or without 200 pM or 20 nM TGF-α. It was found that neither of these TGF-α concentrations affected β-cell mitogenesis, insulin content or insulin secretion. However, IFN-γ (1000 U/ml) evoked a modest stimulation of β-cell replication, while suppressing insulin secretion and leaving the islet insulin content unaltered. TNF-α (1000 U/ml), on the other hand, affected none of these parameters either alone or in any combination with TGF-α or IFN-γ. However, when TNF-α or IFN-γ, either alone or in combination, were combined with the cytokine interleukin-1β, this resulted in islet disintegration, whereas the latter cytokine alone did not exert any gross necrotic changes evident by light microscopy. TGF-β (500 pM) stimulated insulin secretion but did not influence islet insulin content or β-cell mitogenesis either alone or in combination with TGF-α (200 pM or 20 nM). In no instance could any mitogenic or secretory response to low or high concentrations of TGF-α be conferred by IFN-γ, TNF-α or TGF-β whether used alone or in combinations. Hence, responsiveness to TGF-α or EGF in the β-cell obviously cannot be achieved by any of these peptides.

scholarly journals The Effects of Rice Husk Liquid Smoke in Porphyromonas gingivalis-Induced Periodontitis

2021 ◽  
Author(s):  
Theresia Indah Budhy ◽  
Ira Arundina ◽  
Meircurius Dwi Condro Surboyo ◽  
Anisa Nur Halimah
Keyword(s):  
Growth Factor ◽  
Porphyromonas Gingivalis ◽  
Rice Husk ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Control Group ◽  
Proliferation Markers ◽  
Liquid Smoke ◽  
Tnf Α ◽  
Factor Α

Abstract Objectives The purpose of this study is to analyze the effects of rice husk liquid smoke in Porphyromonas gingivalis-induced periodontitis in the inflammatory and proliferation marker such as nuclear factor kappa β (NF-kB), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), transforming growth factor-β (TGF-β), fibroblast growth factor 2 (FGF2), collagen type 1 (COL-1) expression, and the number of macrophages, lymphocytes, and fibroblasts. Materials and Methods Rice husk liquid smoke is obtained by the pyrolysis process. Porphyromonas gingivalis-induced periodontitis in 20 μL phosphate-buffered saline containing 1 × 109 CFU was injected into the lower anterior gingival sulcus of Wistar rats. The periodontitis was then treated with 20 μL/20 g body weight of rice husk liquid smoke once a day for 2 and 7 days, respectively. After treatment, the bone and lower anterior gingival sulcus were analyzed with immunohistochemistry and hematoxylin–eosin staining. Results The treatment of periodontitis with rice husk liquid smoke showed a lower NF-kB, TNF-α, and IL-6 expression and a higher TGF-β, FGF2, and COL-1 expression than the control after treatment for 2 and 7 days (p < 0.05), respectively. The number of macrophages and fibroblasts was also higher when compared with the control group (p < 0.05), but the number of lymphocytes was lower than the control (p < 0.05). Conclusion Rice husk liquid smoke showed its effects on Porphyromonas gingivalis-induced periodontitis with a decrease in inflammatory markers and an increase in proliferation markers. The development of a rice husk liquid smoke periodontitis treatment is promising.

Differential Mechanisms of Plasminogen Activator Inhibitor-1 Gene Activation by Transforming Growth Factor-β and Tumor Necrosis Factor-α in Endothelial Cells

2001 ◽  
Vol 86 (12) ◽  
pp. 1563-1572 ◽  
Author(s):  
Yan Chen ◽  
Joanne Sloan-Lancaster ◽  
David Berg ◽  
Mark Richardson ◽  
Brian Grinnell ◽  
...  
Keyword(s):  
Map Kinases ◽  
Transforming Growth Factor ◽  
Gene Activation ◽  
Plasminogen Activator Inhibitor ◽  
Transforming Growth Factor Β ◽  
Promoter Activation ◽  
Plasminogen Activator Inhibitor 1 ◽  
Tnf Α ◽  
Factor Α ◽  
Pai 1

SummaryPlasminogen activator inhibitor-1 (PAI-1) is a serine protease inhibitor (SERPIN) specific for tissue-type and urokinase-like plasminogen activators. High plasma PAI-1 activity is a risk factor for thrombotic diseases. Due to the short half-life of PAI-1, regulation of PAI-1 gene expression and secretion of active PAI-1 into the blood stream is important for hemostatic balance. We have investigated transcriptional control of PAI-1 gene expression in bovine aortic endothelial cells (BAECs) and human cell lines using PAI-1 5’ promoter-luciferase reporter assays. Contrary to the cytokine-induced up-regulation of PAI-1 mRNA and protein levels, we found that only transforming growth factor-β (TGF-β) was efficient in inducing PAI-1 promoter activation. Tissue necrosis factor-α (TNF-α) induced a small luciferase activity with the 2.5 kb PAI-1 promoter, but not with the PAI-800/4G/5G and p3TP-lux promoters. Next we investigated whether a lack of response to TNF-α was due to deficient signaling pathways. BAECs responded to TNF-α with robust NFκB promoter activation. TGF-β activated the p38 MAP kinase, while TNF-α activated both the SAPK/JNK and p38 MAP kinases. The ERK1/2 MAP kinases were constitutively activated in BAECs. BAEC therefore responded to TNF-α stimulation with activation of the MAP kinases and the NFκB transcriptional factors. We further measured the messenger RNA stability under the influence by TGF-β and TNF-α and found no difference. PAI-1 gene activation by TNF-α apparently is yet to be defined for the location of the response element and/or the signaling pathway, while TGF-β is the most important cytokine for PAI-1 transcriptional activation through its 5’ proximal promoter.

Exposure to febrile temperature modifies endothelial cell response to tumor necrosis factor-α

2001 ◽  
Vol 90 (1) ◽  
pp. 90-98 ◽  
Author(s):  
Jeffrey D. Hasday ◽  
Douglas Bannerman ◽  
Sirhan Sakarya ◽  
Alan S. Cross ◽  
Ishwar S. Singh ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Gm Csf ◽  
Tnf Α ◽  
Neutrophil Adherence ◽  
Endothelial Cell Response ◽  
Factor Α ◽  
Necrosis Factor

Fever is an important regulator of inflammation that modifies expression and bioactivity of cytokines, including tumor necrosis factor (TNF)-α. Pulmonary vascular endothelium is an important target of TNF-α during the systemic inflammatory response. In this study, we analyzed the effect of a febrile range temperature (39.5°C) on TNF-α-stimulated changes in endothelial barrier function, capacity for neutrophil binding and transendothelial migration (TEM), and cytokine secretion in human pulmonary artery endothelial cells (EC). Permeability for [14C]BSA tracer was increased by treatment with TNF-α, and this effect was augmented by incubating EC at 39.5°C. Treating EC with 2.5 U/ml TNF-α stimulated an increase in subsequent neutrophil adherence and TEM. Incubating EC at 39.5°C caused a 30% increase in TEM but did not modify the enhancement of neutrophil adherence or TEM by TNF-α treatment. Analysis of cytokine expression in EC cultures exposed to TNF-α at either 37° or 39.5°C revealed three patterns of temperature and TNF-α responsiveness. Granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin (IL)-8 were not detectable in untreated EC but were increased after TNF-α exposure, and this increase was enhanced at 39.5°C. IL-6 expression was also increased with TNF-α exposure, but IL-6 expression was lower in 39.5°C EC cultures. Transforming growth factor-β1was constitutively expressed, and its expression was not influenced either by TNF-α or exposure to 39.5°C. These data demonstrate that clinically relevant shifts in body temperature might cause important changes in the effects of proinflammatory cytokines on the endothelium.

scholarly journals A mechanism of suppression of TGF–β/SMAD signaling by NF-κB/RelA

2000 ◽  
Vol 14 (2) ◽  
pp. 187-197 ◽  
Author(s):  
Markus Bitzer ◽  
Gero von Gersdorff ◽  
Dan Liang ◽  
Alfredo Dominguez-Rosales ◽  
Amer A. Beg ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Nuclear Translocation ◽  
Transforming Growth Factor Β ◽  
Nuclear Factor Κb ◽  
Transcriptional Responses ◽  
Smad Signaling ◽  
Antisense Mrna ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

A number of pathogenic and proinflammatory stimuli, and the transforming growth factor-β (TGF-β) exert opposing activities in cellular and immune responses. Here we show that the RelA subunit of nuclear factor κB (NF-κB/RelA) is necessary for the inhibition of TGF-β-induced phosphorylation, nuclear translocation, and DNA binding of SMAD signaling complexes by tumor necrosis factor-α (TNF-α). The antagonism is mediated through up-regulation of Smad7 synthesis and induction of stable associations between ligand-activated TGF-β receptors and inhibitory Smad7. Down-regulation of endogenous Smad7 by expression of antisense mRNA releases TGF-β/SMAD-induced transcriptional responses from suppression by cytokine-activated NF-κB/RelA. Following stimulation with bacterial lipopolysaccharide (LPS), or the proinflammatory cytokines TNF-α and interleukin-1β (IL-1β, NF-κB/RelA induces Smad7 synthesis through activation of Smad7 gene transcription. These results suggest a mechanism of suppression of TGF-β/SMAD signaling by opposing stimuli mediated through the activation of inhibitory Smad7 by NF-κB/RelA.

Regulation of intracellular polyamine biosynthesis and transport by NO and cytokines TNF-α and IFN-γ

1999 ◽  
Vol 276 (4) ◽  
pp. C892-C899 ◽  
Author(s):  
Joseph Satriano ◽  
Shunji Ishizuka ◽  
D. Clay Archer ◽  
Roland C. Blantz ◽  
Carolyn J. Kelly
Keyword(s):  
Cellular Proliferation ◽  
Interferon Γ ◽  
Experimental Models ◽  
Proximal Tubule Cell ◽  
Polyamine Biosynthesis ◽  
No Donors ◽  
Temporal Regulation ◽  
Tnf Α ◽  
Ifn Γ ◽  
Factor Α

Nitric oxide (NO) has been described to exert cytostatic effects on cellular proliferation; however the mechanisms responsible for these effects have yet to be fully resolved. Polyamines, conversely, are required components of cellular proliferation. In experimental models of inflammation, a relationship between these two pathways has been suggested by the temporal regulation of a common precursor, arginine. This study was undertaken to determine the effects NO and the NO synthase (NOS)-inducing cytokines, tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), exert on polyamine regulation. The transformed kidney proximal tubule cell line, MCT, maintains high constitutive levels of the first polyamine biosynthetic enzyme, ornithine decarboxylase (ODC). NO donors markedly suppressed ODC activity in MCT and all other cell lines examined. TNF-α and IFN-γ induction of NO generation resulted in suppressed ODC activity, an effect prevented by the inducible NOS inhibitorl- N 6-(1-iminoethyl)lysine (l-NIL). Dithiothreitol reversal of NO-mediated ODC suppression supports nitrosylation as the mechanism of inactivation. We also evaluated polyamine uptake, inasmuch as inhibition of ODC can result in a compensatory induction of polyamine transporters. Administration of NO donors, or TNF-α and IFN-γ, suppressed [3H]putrescine uptake, thereby preventing transport-mediated reestablishment of intracellular polyamine levels. This study demonstrates the capacity of NO and inflammatory cytokines to regulate both polyamine biosynthesis and transport.

Serum and BAL cytokine and antioxidant enzyme levels at different stages of pneumoconiosis in coal workers

2008 ◽  
Vol 27 (12) ◽  
pp. 871-877 ◽  
Author(s):  
OC Ulker ◽  
B Yucesoy ◽  
O Demir ◽  
IO Tekin ◽  
A Karakaya
Keyword(s):  
Antioxidant Enzymes ◽  
Transforming Growth Factor ◽  
Coal Dust ◽  
Transforming Growth Factor Β ◽  
Control Group ◽  
Tnf Α ◽  
Patient Groups ◽  
Coal Workers Pneumoconiosis ◽  
Factor Α ◽  
Coal Workers

Coal workers’ pneumoconiosis (CWP) is an occupational pulmonary disease that occurs by chronic inhalation of coal dust. CWP is divided into two stages depending on the extent of the disease, as simple pneumoconiosis (SP) and progressive massive fibrosis (PMF). In the present study, serum and bronchoalveolar lavage (BAL) cytokine (interleukin-1β [IL-1β], IL-6, tumor necrosis factor-α [TNF-α], transforming growth factor-β [TGF-β]) and antioxidant enzymes levels, their relation with the disease severity, and whether they can be considered as biological markers were investigated. Serum and BAL levels of IL-1β, IL-6, and TNF-α were higher in SP and PMF patient groups compared with that in active and retired miner groups. Serum and BAL IL-1β, IL-6, and TNF-α levels were also found to be higher in patients with PMF compared with the SP group. BAL superoxide dismutase (SOD), glutathione peroxidase, and catalase levels and serum SOD level were increased in both patient groups compared with the control group. In addition, mean serum and BAL TGF-β levels were found to be increased in patients with SP compared with PMF group. Based on these results, BAL and serum cytokine and antioxidant enzymes levels were evaluated and discussed as potential biomarkers for different stages of CWP.

scholarly journals Intracellular Antimicrobial Activity in the Absence of Interferon-γ: Effect of Interleukin-12 in Experimental Visceral Leishmaniasis in Interferon-γ Gene-disrupted Mice

1997 ◽  
Vol 185 (7) ◽  
pp. 1231-1240 ◽  
Author(s):  
Alice P. Taylor ◽  
Henry W. Murray
Keyword(s):  
Antimicrobial Activity ◽  
Visceral Leishmaniasis ◽  
Leishmania Donovani ◽  
Gene Knockout ◽  
Interferon Γ ◽  
Interleukin 12 ◽  
Tnf Α ◽  
Ifn Γ ◽  
Independent Effects ◽  
Factor Α

Despite permitting uncontrolled intracellular visceral infection for 8 wk, interferon-γ (IFN-γ) gene knockout (GKO) mice infected with Leishmania donovani proceeded to reduce liver parasite burdens by 50% by week 12. This late-developing IFN-γ–independent antileishmanial mechanism appeared to be dependent largely on endogenous tumor necrosis factor-α (TNF-α): L. donovani infection induced TNF-α mRNA expression in parasitized GKO livers and neutralization of TNF-α reversed control at week 12. 7 d of treatment of infected GKO mice with interleukin-12 (IL-12) readily induced leishmanicidal activity and also partially restored the near-absent tissue granulomatous response, observations that for the first time expand the antimicrobial repertoire of IL-12 to include IFN-γ–independent effects. The action of IL-12 against L. donovani was TNF-α dependent and required the activity of inducible nitric oxide synthase. These results point to the presence of an IFN-γ–independent antimicrobial mechanism, mediated by TNF-α, which remains quiescent until activated late in the course of experimental visceral leishmaniasis. However, as judged by the effect of exogenous IL-12 this quiescent mechanism can readily be induced to rapidly yield enhanced intracellular antimicrobial activity.

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