scholarly journals Duality of Interactions Between TGF-β and TNF-α During Tumor Formation

2022 ◽  
Vol 12 ◽  
Author(s):  
Zhi-wei Liu ◽  
Yi-ming Zhang ◽  
Li-ying Zhang ◽  
Ting Zhou ◽  
Yang-yang Li ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Transforming Growth Factor ◽  
Biological Activities ◽  
Formation Rate ◽  
Transforming Growth Factor Β ◽  
Immune Serum ◽  
Antagonistic Effect ◽  
Tumor Formation ◽  
Tnf Α ◽  
Wide Range

The tumor microenvironment is essential for the formation and development of tumors. Cytokines in the microenvironment may affect the growth, metastasis and prognosis of tumors, and play different roles in different stages of tumors, of which transforming growth factor β (TGF-β) and tumor necrosis factor α (TNF-α) are critical. The two have synergistic and antagonistic effect on tumor regulation. The inhibition of TGF-β can promote the formation rate of tumor, while TGF-β can promote the malignancy of tumor. TNF-α was initially determined to be a natural immune serum mediator that can induce tumor hemorrhagic necrosis, it has a wide range of biological activities and can be used clinically as a target to immune diseases as well as tumors. However, there are few reports on the interaction between the two in the tumor microenvironment. This paper combs the biological effect of the two in different aspects of different tumors. We summarized the changes and clinical medication rules of the two in different tissue cells, hoping to provide a new idea for the clinical application of the two cytokines.

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.

scholarly journals Differences in the profile of cytokine expression induced by implantation of oncogenic and non-oncogenic millipore filters

2019 ◽  
Vol 6 (3) ◽  
pp. 57-62
Author(s):  
E. Yu. Rybalkina ◽  
O. Yu. Susova ◽  
T. G. Moizhess
Keyword(s):  
Foreign Bodies ◽  
Pore Diameter ◽  
Transforming Growth Factor ◽  
Quantitative Difference ◽  
Transforming Growth Factor Β ◽  
Polymerase Chain Reaction Method ◽  
Tumor Formation ◽  
Signal Molecules ◽  
Tnf Α ◽  
Millipore Filters

Background. Clarification of the mechanisms of carcinogenesis induced by foreign bodies is one of the urgent problems of modern oncology. This is due to the fact that there is a relationship between the processes of inflammation and carcinogenesis. Today, there is no doubt the fact that cytokines and signal molecules in the focus of inflammation (products of inflammation) can contribute to the initiation of carcinogenesis, as well as stimulate tumor progression. In the case of carcinogenesis induced by foreign bodies, the key issue is understanding the differences in the body’s response to the implantation of foreign bodies that can cause tumor formation and do not have this ability. One of the phenomena of this type of carcinogenesis is the occurrence of sarcoma after the subcutaneous implantation in mice of hydrophilic millipore filters with a pore diameter not exceeding 0.1 μm and the inability to induce tumors of one’s with a pore diameter greater than or equal to 0.22 μm.The objective of our work was to study the differences between oncogenic and non-oncogenic filters at the molecular level.Materials and methods. Reverse transcription polymerase chain reaction method was used to study the expression of a number of cytokines that are products of macrophage cells that live on the surface of implanted filters and in the surrounding capsule. Filters with pore diameters of 0.025 μm (carcinogenic) and 0.45 μm (non-carcinogenic) were compared in 8, 35 days and 5.5 months after implantation.Results and conclusion. After 8 days we observed significant (p <0.01) excess of expression of two cytokines interleukin 1β (IL-1β) by cells around oncogenic filters (with pore of 0.025 μm) compared to non-oncogenic one’s (with pore of 0.45 μm) After 35 days, significant (p <0.01) excess of expression of IL-1β, Tnf-α, iNOS (induced nitric oxide synthase), and IL-6 by cells around the oncogenic filters (0.025 μm) compared to non-oncogenic one’s (0.45 μm) was observed. There was no quantitative difference in the expression of Nf-κB1 and Nf-κB2 (nuclear factor κ-B1, κ-B2), Tgf-β (transforming growth factor β), IL-10. After 5.5 months the expression of IL-1β by cells on oncogenic filters was still significant; for Tnf-α, iNOS, IL-6 and IL-10 there was no practically difference in expression. For Nf-κB1 and Nf-κB2, Tgf-β and COX-2 (cyclooxygenase 2) the difference was significant, cells on non-oncogenic filters are expressed more then on oncogenic one’s.

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.

scholarly journals Advances in the Development Ubiquitin-Specific Peptidase (USP) Inhibitors

2021 ◽  
Vol 22 (9) ◽  
pp. 4546
Author(s):  
Shiyao Chen ◽  
Yunqi Liu ◽  
Huchen Zhou
Keyword(s):  
Signaling Pathways ◽  
Transforming Growth Factor ◽  
Regulatory System ◽  
Transforming Growth Factor Β ◽  
Molecular Signaling ◽  
Post Translational Modification ◽  
The Past ◽  
Damage Repair ◽  
Wide Range ◽  
Cancer And Inflammation

Ubiquitylation and deubiquitylation are reversible protein post-translational modification (PTM) processes involving the regulation of protein degradation under physiological conditions. Loss of balance in this regulatory system can lead to a wide range of diseases, such as cancer and inflammation. As the main members of the deubiquitinases (DUBs) family, ubiquitin-specific peptidases (USPs) are closely related to biological processes through a variety of molecular signaling pathways, including DNA damage repair, p53 and transforming growth factor-β (TGF-β) pathways. Over the past decade, increasing attention has been drawn to USPs as potential targets for the development of therapeutics across diverse therapeutic areas. In this review, we summarize the crucial roles of USPs in different signaling pathways and focus on advances in the development of USP inhibitors, as well as the methods of screening and identifying USP inhibitors.

TGFβ: Signaling Blockade for Cancer Immunotherapy

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Szu-Ying Chen ◽  
Ons Mamäi ◽  
Rosemary J. Akhurst
Keyword(s):  
Cancer Biology ◽  
Transforming Growth Factor ◽  
Biological Activities ◽  
Tumor Stroma ◽  
Transforming Growth Factor Β ◽  
Therapeutic Window ◽  
Annual Review ◽  
Publication Date ◽  
Tgfβ Signaling ◽  
Mesenchymal Transformation

Discovered over four decades ago, transforming growth factor β (TGFβ) is a potent pleiotropic cytokine that has context-dependent effects on most cell types. It acts as a tumor suppressor in some cancers and/or supports tumor progression and metastasis through its effects on the tumor stroma and immune microenvironment. In TGFβ-responsive tumors it can promote invasion and metastasis through epithelial-mesenchymal transformation, the appearance of cancer stem cell features, and resistance to many drug classes, including checkpoint blockade immunotherapies. Here we consider the biological activities of TGFβ action on different cells of relevance toward improving immunotherapy outcomes for patients, with a focus on the adaptive immune system. We discuss recent advances in the development of drugs that target the TGFβ signaling pathway in a tumor-specific or cell type–specific manner to improve the therapeutic window between response rates and adverse effects. Expected final online publication date for the Annual Review of Cancer Biology, Volume 6 is April 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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.

Upregulation of osteopontin expression is involved in the development of nonalcoholic steatohepatitis in a dietary murine model

2004 ◽  
Vol 287 (1) ◽  
pp. G264-G273 ◽  
Author(s):  
Atul Sahai ◽  
Padmini Malladi ◽  
Hector Melin-Aldana ◽  
Richard M. Green ◽  
Peter F. Whitington
Keyword(s):  
Oxidative Stress ◽  
Mrna Expression ◽  
Nonalcoholic Steatohepatitis ◽  
Transforming Growth Factor ◽  
Control Diet ◽  
Transforming Growth Factor Β ◽  
Collagen I ◽  
Tnf Α ◽  
Th1 Cytokine

The pathogenesis of nonalcoholic steatohepatitis (NASH) is poorly defined. Feeding mice a diet deficient in methionine and choline (MCD diet) induces experimental NASH. Osteopontin (OPN) is a Th1 cytokine that plays an important role in several fibroinflammatory diseases. We examined the role of OPN in the development of experimental NASH. A/J mice were fed MCD or control diet for up to 12 wk, and serum alanine aminotransferase (ALT), liver histology, oxidative stress, and the expressions of OPN, TNF-α, and collagen I were assessed at various time points. MCD diet-fed mice developed hepatic steatosis starting after 1 wk and inflammation by 2 wk; serum ALT increased from day 3. Hepatic collagen I mRNA expression increased during 1–4 wk, and fibrosis appeared at 8 wk. OPN protein expression was markedly increased on day 1 of MCD diet and persisted up to 8 wk, whereas OPN mRNA expression was increased at week 4. TNF-α expression was increased from day 3 to 2 wk, and evidence of oxidative stress did not appear until 8 wk. Increased expression of OPN was predominantly localized in hepatocytes. Hepatocytes in culture also produced OPN, which was stimulated by transforming growth factor-β and TNF-α. Moreover, MCD diet-induced increases in serum ALT levels, hepatic inflammation, and fibrosis were markedly reduced in OPN−/− mice when compared with OPN+/+ mice. In conclusion, our results demonstrate an upregulation of OPN expression early in the development of steatohepatitis and suggest an important role for OPN in signaling the onset of liver injury and fibrosis in experimental NASH.

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.

208 EFFECT OF GDF8 AND SB-431542 ON PORCINE OOCYTE DURING IN VITRO MATURATION AND SUBSEQUENT EMBRYONIC DEVELOPMENT

2016 ◽  
Vol 28 (2) ◽  
pp. 235
Author(s):  
J. D. Yoon ◽  
E. Lee ◽  
S.-H. Hyun
Keyword(s):  
Treatment Group ◽  
Embryonic Development ◽  
Follicular Fluid ◽  
In Vitro Maturation ◽  
Transforming Growth Factor ◽  
Formation Rate ◽  
Transforming Growth Factor Β ◽  
Nuclear Maturation ◽  
Porcine Oocyte

Growth differentiation factor-8 (GDF8) is a member of the transforming growth factor-β that has been identified as a strong physiological regulator. SB-431542 (SB) is a specific inhibitor of transforming growth factor-β superfamily type I activin receptor-like kinase (ALK) receptors such as ALK4, ALK5, and ALK7. The purpose of this study is investigation of the effects of GDF8 and SB on porcine oocytes during in vitro maturation and subsequent embryonic development. We first performed ELISA to detect GDF8 concentrations in follicular fluid for each size of follicle; sizes were as follows: small (<3 mm), medium (>3 mm and <6 mm), and large (>6 mm) follicle. After detection of the GDF8 concentration in follicular fluid, we investigated the effect of GDF8 and SB treatment during in vitro maturation (IVM) on nuclear maturation, intracellular glutathione (GSH), and reactive oxygen species (ROS) levels, and embryonic development after IVF and parthenogenetic activation (PA). Data were analysed by ANOVA followed by Duncan using SPSS (Statistical Package for Social Science, IBM, New York, NY, USA) mean ± SEM. The ELISA result showed different concentrations of GDF8 for each grade of follicular fluid: small, 0.479 ng mL–1; medium, 0.668 ng mL–1; and large, 1.318 ng mL–1. During the IVM process, 1.318 ng mL–1 of GDF8 and 5 ng mL–1 of SB were added to the maturation medium as control, SB, SB+GDF8, and GDF8 treatment groups. After 44 h of IVM, GDF8 group (90.4%) showed a significantly higher nuclear maturation rate than control and SB+GDF8 groups (85.4 and 81.7%). The SB group (78.9%) showed significantly reduced nuclear maturation rate compared with control (P < 0.05). The GDF8 treatment group showed a significant decreased intracellular ROS and increased GSH levels compared with other groups (P < 0.05). The SB+GBF8 treatment group showed a significantly better cytoplasmic maturation than the SB treatment group. In the PA embryonic development analysis, the GDF8 treatment group showed a significantly higher blastocyst formation rate compared with other groups (47.9, 37.2, 46.4, and 58.7% respectively; P < 0.05). In the IVF embryonic development analysis, the GDF8 treatment groups showed significantly higher blastocyst formation rate compared with the SB group (28.2 and 42.2%, respectively; P < 0.05). In conclusion, treatment with GDF8 during porcine oocyte IVM improved the embryonic developmental competence via increased cytoplasmic maturation and led to better oocyte maturation from the ALK receptor inhibition by SB.

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