scholarly journals Endotoxin-Induced Endothelial Fibrosis Is Dependent on Expression of Transforming Growth Factors β1 and β2

2014 ◽  
Vol 82 (9) ◽  
pp. 3678-3686 ◽  
Author(s):  
César Echeverría ◽  
Ignacio Montorfano ◽  
Pablo Tapia ◽  
Claudia Riedel ◽  
Claudio Cabello-Verrugio ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Inflammatory Diseases ◽  
Vascular Dysfunction ◽  
Transforming Growth Factor Β1 ◽  
Protein Expression Pattern ◽  
Bacterial Endotoxins ◽  
Β Receptor ◽  
Activated Fibroblasts ◽  
Induced Changes ◽  
Tgf Β1

ABSTRACTDuring endotoxemia-induced inflammatory disease, bacterial endotoxins circulate in the bloodstream and interact with endothelial cells (ECs), inducing dysfunction of the ECs. We previously reported that endotoxins induce the conversion of ECs into activated fibroblasts. Through endotoxin-induced endothelial fibrosis, ECs change their morphology and their protein expression pattern, thereby suppressing endothelial markers and upregulating fibrotic proteins. The most commonly used fibrotic inducers are transforming growth factor β1 (TGF-β1) and TGF-β2. However, whether TGF-β1 and TGF-β2 participate in endotoxin-induced endothelial fibrosis remains unknown. We have shown that the endotoxin-induced endothelial fibrosis process is dependent on the TGF-β receptor, ALK5, and the activation of Smad3, a protein that is activated by ALK5 activation, thus suggesting that endotoxin elicits TGF-β production to mediate endotoxin-induced endothelial fibrosis. Therefore, we investigated the dependence of endotoxin-induced endothelial fibrosis on the expression of TGF-β1 and TGF-β2. Endotoxin-treated ECs induced the expression and secretion of TGF-β1 and TGF-β2. TGF-β1 and TGF-β2 downregulation inhibited the endotoxin-induced changes in the endothelial marker VE-cadherin and in the fibrotic proteins α-SMA and fibronectin. Thus, endotoxin induces the production of TGF-β1 and TGF-β2 as a mechanism to promote endotoxin-induced endothelial fibrosis. To the best of our knowledge, this is the first report showing that endotoxin induces endothelial fibrosis via TGF-β secretion, which represents an emerging source of vascular dysfunction. These findings contribute to understanding the molecular mechanism of endotoxin-induced endothelial fibrosis, which could be useful in the treatment of inflammatory diseases.

Receptor mimicking TGF-β1 binding peptide for targeting TGF-β1 signaling

2021 ◽  
Author(s):  
David G. Belair ◽  
Jae Sung Lee ◽  
Anna V. Kellner ◽  
Johnny Huard ◽  
William L. Murphy
Keyword(s):  
Biological Activity ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Soluble Form ◽  
Receptor Complex ◽  
Binding Peptide ◽  
Binding Peptides ◽  
Β Receptor ◽  
Tgf Β1

Transforming growth factor-β1 (TGF-β1) binding peptides were developed via biomimicry of the TGF-β1/TGF-β receptor complex to attenuate biological activity of TGF-β1 when presented either in soluble form or conjugated to synthetic biomaterials.

Transforming Growth Factor-β1 (TGF-β1) Induces Thrombopoietin From Bone Marrow Stromal Cells, Which Stimulates the Expression of TGF-β Receptor on Megakaryocytes and, in Turn, Renders Them Susceptible to Suppression by TGF-β Itself With High Specificity

Blood ◽  
1999 ◽  
Vol 94 (6) ◽  
pp. 1961-1970 ◽  
Author(s):  
Sumio Sakamaki ◽  
Yasuo Hirayama ◽  
Takuya Matsunaga ◽  
Hiroyuki Kuroda ◽  
Toshiro Kusakabe ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
High Specificity ◽  
Transforming Growth Factor Β1 ◽  
Lineage Specificity ◽  
Β Receptor ◽  
Tgf Β1

Abstract The present study was designed to test the concept that platelets release a humoral factor that plays a regulatory role in megakaryopoiesis. The results showed that, among various hematoregulatory cytokines examined, transforming growth factor-β1 (TGF-β1) was by far the most potent enhancer of mRNA expression of bone marrow stromal thrombopoietin (TPO), a commitment of lineage specificity. The TPO, in turn, induced TGF-β receptors I and II on megakaryoblasts at the midmegakaryopoietic stage; at this stage, TGF-β1 was able to arrest the maturation of megakaryocyte colony-forming units (CFU-Meg). This effect was relatively specific when compared with its effect on burst-forming unit-erythroid (BFU-E) or colony-forming unit–granulocyte-macrophage (CFU-GM). In patients with idiopathic thrombocytopenic purpura (ITP), the levels of both TGF-β1 and stromal TPO mRNA were correlatively increased and an arrest of megakaryocyte maturation was observed. These in vivo findings are in accord with the aforementioned in vitro results. Thus, the results of the present investigation suggest that TGF-β1 is one of the pathophysiological feedback regulators of megakaryopoiesis.

scholarly journals Involvement of Smad7 in Inflammatory Diseases of the Gut and Colon Cancer

2021 ◽  
Vol 22 (8) ◽  
pp. 3922
Author(s):  
Edoardo Troncone ◽  
Irene Marafini ◽  
Carmine Stolfi ◽  
Giovanni Monteleone
Keyword(s):  
Transforming Growth Factor ◽  
Intestinal Inflammation ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Cell Types ◽  
Transforming Growth Factor Β1 ◽  
Cancer Prognosis ◽  
Refractory Celiac Disease ◽  
Bowel Diseases ◽  
Tgf Β1

In physiological conditions, the human intestinal mucosa is massively infiltrated with various subsets of immune cells, the activity of which is tightly regulated by several counter-regulatory factors. One of these factors is transforming growth factor-β1 (TGF-β1), a cytokine produced by multiple cell types and targeting virtually all the intestinal mucosal cells. Binding of TGF-β1 to its receptors triggers Smad2/3 signaling, thus culminating in the attenuation/suppression of immune–inflammatory responses. In patients with Crohn’s disease and patients with ulcerative colitis, the major human inflammatory bowel diseases (IBD), and in mice with IBD-like colitis, there is defective TGF-β1/Smad signaling due to high levels of the intracellular inhibitor Smad7. Pharmacological inhibition of Smad7 restores TGF-β1 function, thereby reducing inflammatory pathways in patients with IBD and colitic mice. On the other hand, transgenic over-expression of Smad7 in T cells exacerbates colitis in various mouse models of IBD. Smad7 is also over-expressed in other inflammatory disorders of the gut, such as refractory celiac disease, necrotizing enterocolitis and cytomegalovirus-induced colitis, even though evidence is still scarce and mainly descriptive. Furthermore, Smad7 has been involved in colon carcinogenesis through complex and heterogeneous mechanisms, and Smad7 polymorphisms could influence cancer prognosis. In this article, we review the data about the expression and role of Smad7 in intestinal inflammation and cancer.

scholarly journals Adhatoda Vasica: a potential ayurvedic intervention against COVID-19 associated impaired immune response and hypoxia-inflammation phenotype

2020 ◽  
Author(s):  
Atish Gheware ◽  
Dhwani Dholakia ◽  
S. Kannan ◽  
Lipsa Panda ◽  
Vivek Anand ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Viral Entry ◽  
Transforming Growth Factor ◽  
Inflammatory Diseases ◽  
Hypoxia Inducible Factor ◽  
Transforming Growth Factor Β1 ◽  
Infection And Inflammation ◽  
Impaired Immune Response ◽  
Anti Inflammatory ◽  
Tgf Β1

Abstract Background: The importance of hypoxia inducible factor-1 α (HIF-1α) stabilization in uncontrolled infection and inflammation is widely accepted. Several inhibitors of HIF signalling are in clinical trials for malignancy, ischemia and inflammatory diseases. Increased hypoxia is being reported to be an important modifier for several pathological features of COVID-19 such as impaired immunity, hyper-inflammation, thrombosis, lung injury and sepsis. Methods: In this study we tested the effect of whole aqueous extract Adhatoda Vasica (AV), that our group has shown to have anti-hypoxic and anti-inflammatory effects, on various outcomes of hypoxic response. Effects of AV were assessed in preclinical mouse models of pulmonary fibrosis, bacterial sepsis and siRNA induced hypoxia-thrombosis phenotype. Therapeutic relevance of AV in current pandemic were also examined through transcriptome and molecular docking analysis. Results: Oral administration AV extract attenuated the increased levels of airway inflammation, collagen content, transforming growth factor-β1 (TGF-β1), IL-6, HIF-1α and improved the overall survival rate in bleomycin treated and Cecum Ligation and Puncture (CLP) induced mice. AV treatment also rescued the prolyl hydroxylase domain 2 (phd2) siRNA induced HIF-1α and associated blood coagulation phenotypes in mice. Transcriptome analysis of lungs of AV treated naïve mice reveal downregulation of hypoxia, inflammation, TGF-β1 and angiogenesis and upregulation of adaptive immunity related genes. These genes and pathways show opposite expression in transcriptome of BALF and PBMCs of SARS-CoV2 infected patient. Molecular docking of AV constituents presents in extract reveal many molecules with low binding energy (≤ -8) to multiple SARS-CoV2 and host target proteins that are relevant in viral entry and replication. Conclusion: Our results provide a scientific rationale for this ayurvedic herbal medicine in ameliorating the anti-inflammatory and anti-HIF-1α effect for potential use in management of COVID19 patients.

scholarly journals Gene expression profiling demonstrates that TGF-β1 signals exclusively through receptor complexes involving Alk5 and identifies targets of TGF-β signaling

2005 ◽  
Vol 21 (3) ◽  
pp. 396-403 ◽  
Author(s):  
Göran Karlsson ◽  
Yingchun Liu ◽  
Jonas Larsson ◽  
Marie-José Goumans ◽  
Ju-Seog Lee ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Cellular Functions ◽  
Murine Embryonic Fibroblast ◽  
Downstream Signaling ◽  
Receptor Complexes ◽  
Downstream Effector ◽  
Β Receptor ◽  
Embryonic Fibroblast ◽  
Tgf Β1

Transforming growth factor-β1 (TGF-β) regulates cellular functions like proliferation, differentiation, and apoptosis. On the cell surface, TGF-β binds to receptor complexes consisting of TGF-β receptor type II (TβRII) and activin-like kinase receptor-5 (Alk5), and the downstream signaling is transduced by Smad and MAPK proteins. Recent data have shown that alternative receptor combinations aside from the classical pairing of TβRII/Alk5 can be relevant for TGF-β signaling. We have screened for alternative receptors for TGF-β and also for gene targets of TGF-β signaling, by performing functional assays and microarray analysis in murine embryonic fibroblast (MEF) cell lines lacking Alk5. Data from TGF-β-stimulated Alk5−/− cells show them to be completely unaffected by TGF-β. Additionally, 465 downstream targets of Alk5 signaling were identified when comparing Alk5−/− or TGF-β-stimulated Alk5+/+ MEFs with unstimulated Alk5+/+ cells. Our results demonstrate that, in MEFs, TGF-β signals exclusively through complexes involving Alk5, and give insight to its downstream effector genes.

scholarly journals Laminin γ2–mediating T cell exclusion attenuates response to anti–PD-1 therapy

2021 ◽  
Vol 7 (6) ◽  
pp. eabc8346 ◽  
Author(s):  
Lei Li ◽  
Jia-Ru Wei ◽  
Jun Dong ◽  
Qing-Guang Lin ◽  
Hong Tang ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptors ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Mouse Tumor ◽  
Chemotherapy Drugs ◽  
T Cell Infiltration ◽  
Clinical Benefits ◽  
Β Receptor ◽  
Tgf Β1

PD-1/PD-L1 blockade therapies provide notable clinical benefits for patients with advanced cancers, but the factors influencing the effectiveness of the treatment remain incompletely cataloged. Here, the up-regulation of laminin γ2 (Ln-γ2) predicted the attenuated efficacy of anti–PD-1 drugs and was associated with unfavorable outcomes in patients with lung cancer or esophageal cancer. Furthermore, Ln-γ2 was transcriptionally activated by transforming growth factor–β1 (TGF-β1) secreted from cancer-associated fibroblasts via JNK/AP1 signaling, which blocked T cell infiltration into the tumor nests by altering the expression of T cell receptors. Coadministration of the TGF-β receptor inhibitor galunisertib and chemotherapy drugs provoked vigorous antitumor activity of anti–PD-1 therapy in mouse tumor models. Therefore, Ln-γ2 may represent a useful biomarker to optimize clinical decisions and predict the response of cancer patients to treatment with anti–PD-1 drugs.

Modulation of Sensitivity to Transforming Growth Factor-β1 (TGF-β1) and the Level of Type II TGF-β Receptor in LNCaP Cells by Dihydrotestosterone

1996 ◽  
Vol 222 (1) ◽  
pp. 103-110 ◽  
Author(s):  
Isaac Yi Kim ◽  
David J. Zelner ◽  
Julia A. Sensibar ◽  
Han-Jong Ahn ◽  
Linda Park ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Type Ii ◽  
Lncap Cells ◽  
Β Receptor ◽  
Tgf Β1

Transforming Growth Factor-β1 (TGF-β1) Induces Thrombopoietin From Bone Marrow Stromal Cells, Which Stimulates the Expression of TGF-β Receptor on Megakaryocytes and, in Turn, Renders Them Susceptible to Suppression by TGF-β Itself With High Specificity

Blood ◽  
1999 ◽  
Vol 94 (6) ◽  
pp. 1961-1970 ◽  
Author(s):  
Sumio Sakamaki ◽  
Yasuo Hirayama ◽  
Takuya Matsunaga ◽  
Hiroyuki Kuroda ◽  
Toshiro Kusakabe ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
High Specificity ◽  
Transforming Growth Factor Β1 ◽  
Lineage Specificity ◽  
Β Receptor ◽  
Tgf Β1

The present study was designed to test the concept that platelets release a humoral factor that plays a regulatory role in megakaryopoiesis. The results showed that, among various hematoregulatory cytokines examined, transforming growth factor-β1 (TGF-β1) was by far the most potent enhancer of mRNA expression of bone marrow stromal thrombopoietin (TPO), a commitment of lineage specificity. The TPO, in turn, induced TGF-β receptors I and II on megakaryoblasts at the midmegakaryopoietic stage; at this stage, TGF-β1 was able to arrest the maturation of megakaryocyte colony-forming units (CFU-Meg). This effect was relatively specific when compared with its effect on burst-forming unit-erythroid (BFU-E) or colony-forming unit–granulocyte-macrophage (CFU-GM). In patients with idiopathic thrombocytopenic purpura (ITP), the levels of both TGF-β1 and stromal TPO mRNA were correlatively increased and an arrest of megakaryocyte maturation was observed. These in vivo findings are in accord with the aforementioned in vitro results. Thus, the results of the present investigation suggest that TGF-β1 is one of the pathophysiological feedback regulators of megakaryopoiesis.

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