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 Osteoarthritic Synovial Fluid and TGF-β1 Induce Interleukin-18 in Articular Chondrocytes

Cartilage ◽  
2018 ◽  
Vol 11 (3) ◽  
pp. 385-394 ◽  
Author(s):  
Camila B. Carballo ◽  
Thiago R. P. Coelho ◽  
Rosenilde C. de Holanda Afonso ◽  
Jane Cristina de Oliveira Faria ◽  
Tercia Alves ◽  
...  
Keyword(s):  
Synovial Fluid ◽  
Transforming Growth Factor ◽  
Articular Chondrocytes ◽  
Inflammatory Responses ◽  
Transforming Growth Factor Β1 ◽  
Receptor Expression ◽  
Interleukin 18 ◽  
Viability Analysis ◽  
Pathophysiological Condition ◽  
Tgf Β1

Objective Synovial fluid (SF) plays an important role in the maintenance of articular cartilage. SF is a dynamic reservoir of proteins derived from cartilage and synovial tissue; thus, its composition may serve as a biomarker that reflects the health and pathophysiological condition of the joint. The purpose of the current study was to evaluate the osteoarthritic synovial fluid (OASF) and transforming growth factor-β1 (TGF-β1) activity in articular chondrocytes catabolic and inflammatory responses. Design Chondrocytes were seeded at passage 2 and cultured for 72 hours under different conditions. Human chondrocytes were subjected to OASF while rat chondrocytes were subjected to either healthy synovial fluid (rSF) or TGF-β1 and then assigned for cell viability analysis. In addition, the effects of OASF and TGF-β1 on chondrocytes metalloprotease (MMP)-3 and MMP-13 and interleukin-18 (IL-18) expression were evaluated by immunocytochemistry, ELISA, and reverse transcriptase-polymerase chain reaction. Results SF from osteoarthritic patients significantly induced MMP-3, MMP-13, and IL-18 receptor expression in chondrocytes. To put in evidence the inflammatory activity of OASF, healthy chondrocytes from rat were cultured with TGF-β1. In the presence of TGF-β1 these cells started to express MMP-3, MMP-13, and IL-18 genes and attached to each other forming a chondrocyte aggregated structure. Healthy SF was able to maintain a typical monolayer of rounded chondrocytes with no inflammatory response. Conclusion In summary, these observations demonstrated that TGF-β1, one of the components of OASF, has a dual effect, acting in chondrocyte maintenance and also inducing inflammatory and catabolic properties of these cells.

scholarly journals Identification of Axl as a downstream effector of TGF-β1 during Langerhans cell differentiation and epidermal homeostasis

2012 ◽  
Vol 209 (11) ◽  
pp. 2033-2047 ◽  
Author(s):  
Thomas Bauer ◽  
Anna Zagórska ◽  
Jennifer Jurkin ◽  
Nighat Yasmin ◽  
René Köffel ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Apoptotic Cell ◽  
Skin Inflammation ◽  
Transforming Growth Factor Β1 ◽  
Epidermal Keratinocytes ◽  
Human Epidermal Keratinocytes ◽  
And Function ◽  
Tgf Β1

Transforming growth factor-β1 (TGF-β1) is a fundamental regulator of immune cell development and function. In this study, we investigated the effects of TGF-β1 on the differentiation of human Langerhans cells (LCs) and identified Axl as a key TGF-β1 effector. Axl belongs to the TAM (Tyro3, Axl, and Mer) receptor tyrosine kinase family, whose members function as inhibitors of innate inflammatory responses in dendritic cells and are essential to the prevention of lupus-like autoimmunity. We found that Axl expression is induced by TGF-β1 during LC differentiation and that LC precursors acquire Axl early during differentiation. We also describe prominent steady-state expression as well as inflammation-induced activation of Axl in human epidermal keratinocytes and LCs. TGF-β1–induced Axl enhances apoptotic cell (AC) uptake and blocks proinflammatory cytokine production. The antiinflammatory role of Axl in the skin is reflected in a marked impairment of the LC network preceding spontaneous skin inflammation in mutant mice that lack all three TAM receptors. Our findings highlight the importance of constitutive Axl expression to tolerogenic barrier immunity in the epidermis and define a mechanism by which TGF-β1 enables silent homeostatic clearing of ACs to maintain long-term self-tolerance.

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.

scholarly journals Transforming growth factor β1 protein and mRNA levels in inflammatory bowel diseases: towards solving the contradictions by longitudinal assessment of the protein and mRNA amounts.

1970 ◽  
Vol 60 (4) ◽  
Author(s):  
Anna Liberek ◽  
Zbigniew Kmieć ◽  
Piotr M Wierzbicki ◽  
Joanna Jakóbkiewicz-Banecka ◽  
Tomasz Liberek ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Mrna Levels ◽  
Longitudinal Assessment ◽  
Active Stage ◽  
Intestinal Tissue ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
Tgf Β1

Previously published studies on levels of the transforming growth factor-β1 (TGF-β1) protein and mRNA of the corresponding gene in patients suffering from inflammatory bowel diseases (IBD) gave varying results, leading to contradictory conclusions. To solve the contradictions, we aimed to assess longitudinally TGF-β1 protein and mRNA levels at different stages of the disease in children suffering from IBD. The study group consisted of 19 pediatric patients with IBD at the age between 3.5 and 18.4 years. The control group consisted of 42 children aged between 2.0 and 18.0 years. The plasma TGF-β1 concentration was measured with ELISA. mRNA levels of the TGF-β1 gene isolated from samples of the intestinal tissue were assessed by reverse transcription and real-time PCR. Levels of TGF-β1 protein in plasma and corresponding mRNA in intestinal tissue were significantly higher in IBD patients than in controls. TGF-β1 and corresponding transcripts were also more abundant in plasma and intestinal tissue, respectively, in patients at the active stage of the disease than during remission. In every single IBD patient, plasma TGF-β1 level and mRNA level in intestinal tissue was higher at the active stage of the disease than during remission. Levels of TGF-β1 and corresponding mRNA are elevated during the active stage of IBD but not during the remission. Longitudinal assessment of this cytokine in a single patient may help to monitor the clinical course of IBD.

scholarly journals Role of TGF-Beta and Smad7 in Gut Inflammation, Fibrosis and Cancer

Biomolecules ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 17
Author(s):  
Carmine Stolfi ◽  
Edoardo Troncone ◽  
Irene Marafini ◽  
Giovanni Monteleone
Keyword(s):  
Transforming Growth Factor ◽  
Cell Types ◽  
Mucosal Immune Response ◽  
The Body ◽  
Mucosal Cell ◽  
Gut Inflammation ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
Tgf Β1

The human gastrointestinal tract contains the largest population of immune cells in the body and this is a reflection of the fact that it is continuously exposed to a myriad of dietary and bacterial antigens. Although these cells produce a variety of inflammatory cytokines that could potentially promote tissue damage, in normal conditions the mucosal immune response is tightly controlled by counter-regulatory factors, which help induce and maintain gut homeostasis and tolerance. One such factor is transforming growth factor (TGF)-β1, a cytokine produced by multiple lineages of leukocytes, stromal cells and epithelial cells, and virtually targets all the gut mucosal cell types. Indeed, studies in animals and humans have shown that defects in TGF-β1 production and/or signaling can lead to the development of immune-inflammatory pathologies, fibrosis and cancer in the gut. Here, we review and discuss the available evidence about the role of TGF-β1 and Smad7, an inhibitor of TGF-β1 activity, in gut inflammation, fibrosis and cancer with particular regard to the contribution of these two molecules in the pathogenesis of inflammatory bowel diseases and colon cancer.

scholarly journals In vitro and in vivo evidence for shear-induced activation of latent transforming growth factor-β1

Blood ◽  
2008 ◽  
Vol 112 (9) ◽  
pp. 3650-3660 ◽  
Author(s):  
Jasimuddin Ahamed ◽  
Nathalie Burg ◽  
Keiji Yoshinaga ◽  
Christin A. Janczak ◽  
Daniel B. Rifkin ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Thrombus Formation ◽  
Cell Types ◽  
Transforming Growth Factor Β1 ◽  
Disulfide Exchange ◽  
Before And After ◽  
Tgf Β1

Transforming growth factor-β1 (TGF-β1) has potent physiologic and pathologic effects on a variety of cell types at subnanomolar concentrations. Platelets contain 40 times as much TGF-β1 as other cells and secrete it as an inactive (latent) form in complex with latency-associated peptide (LAP), which is disulfide bonded via Cys33 to latent TGF-β binding protein 1 (LTBP-1). Little is known about how latent TGF-β1 becomes activated in vivo. Here we show that TGF-β1 released from platelets or fibroblasts undergoes dramatic activation when subjected to stirring or shear forces, providing a potential mechanism for physiologic control. Thiol-disulfide exchange appears to contribute to the process based on the effects of thiol-reactive reagents and differences in thiol labeling of TGF-β1 before and after stirring or shear. Activation required the presence of LTBP, as TGF-β1 contained in complex with only LAP could not be activated by stirring when studied as either a recombinant purified protein complex or in the platelet releasates or sera of mice engineered to contain an LAP C33S mutation. Release and activation of latent TGF-β1 in vivo was demonstrated in a mouse model 5 minutes after thrombus formation. These data potentially provide a novel mechanism for in vivo activation of TGF-β1.

scholarly journals Bone marrow stromal cells induce an ALDH+ stem cell-like phenotype and enhance therapy resistance in AML through a TGF-β-p38-ALDH2 pathway

PLoS ONE ◽  
2020 ◽  
Vol 15 (11) ◽  
pp. e0242809
Author(s):  
Bin Yuan ◽  
Fouad El Dana ◽  
Stanley Ly ◽  
Yuanqing Yan ◽  
Vivian Ruvolo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stromal Cells ◽  
Transforming Growth Factor ◽  
Chemotherapy Resistance ◽  
Cell Types ◽  
Therapy Resistance ◽  
Gene Signature ◽  
Transforming Growth Factor Β1 ◽  
Aldh Activity ◽  
Tgf Β1

The bone marrow microenvironment (BME) in acute myeloid leukemia (AML) consists of various cell types that support the growth of AML cells and protect them from chemotherapy. Mesenchymal stromal cells (MSCs) in the BME have been shown to contribute immensely to leukemogenesis and chemotherapy resistance in AML cells. However, the mechanism of stroma-induced chemotherapy resistance is not known. Here, we hypothesized that stromal cells promote a stem-like phenotype in AML cells, thereby inducing tumorigenecity and therapy resistance. To test our hypothesis, we co-cultured AML cell lines and patient samples with BM-derived MSCs and determined aldehyde dehydrogenase (ALDH) activity and performed gene expression profiling by RNA sequencing. We found that the percentage of ALDH+ cells increased dramatically when AML cells were co-cultured with MSCs. However, among the 19 ALDH isoforms, ALDH2 and ALDH1L2 were the only two that were significantly upregulated in AML cells co-cultured with stromal cells compared to cells cultured alone. Mechanistic studies revealed that the transforming growth factor-β1 (TGF-β1)-regulated gene signature is activated in AML cells co-cultured with MSCs. Knockdown of TGF-β1 in BM-MSCs inhibited stroma-induced ALDH activity and ALDH2 expression in AML cells, whereas treatment with recombinant TGF-β1 induced the ALDH+ phenotype in AML cells. We also found that TGF-β1-induced ALDH2 expression in AML cells is mediated by the non-canonical pathway through the activation of p38. Interestingly, inhibition of ALDH2 with diadzin and CVT-10216 significantly inhibited MSC-induced ALDH activity in AML cells and sensitized them to chemotherapy, even in the presence of MSCs. Collectively, BM stroma induces ALDH2 activity in AML cells through the non-canonical TGF-β pathway. Inhibition of ALDH2 sensitizes AML cells to chemotherapy.

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 Transforming Growth Factor-β1 to the Bone

2005 ◽  
Vol 26 (6) ◽  
pp. 743-774 ◽  
Author(s):  
Katrien Janssens ◽  
Peter ten Dijke ◽  
Sophie Janssens ◽  
Wim Van Hul
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Cell Types ◽  
Transforming Growth Factor Β1 ◽  
Dynamic Processes ◽  
Skeletal Tissue ◽  
The Subject ◽  
Different Cell Types ◽  
Tgf Β1 ◽  
Multifunctional Cytokine

TGF-β1 is a ubiquitous growth factor that is implicated in the control of proliferation, migration, differentiation, and survival of many different cell types. It influences such diverse processes as embryogenesis, angiogenesis, inflammation, and wound healing. In skeletal tissue, TGF-β1 plays a major role in development and maintenance, affecting both cartilage and bone metabolism, the latter being the subject of this review. Because it affects both cells of the osteoblast and osteoclast lineage, TGF-β1 is one of the most important factors in the bone environment, helping to retain the balance between the dynamic processes of bone resorption and bone formation. Many seemingly contradictory reports have been published on the exact functioning of TGF-β1 in the bone milieu. This review provides an overall picture of the bone-specific actions of TGF-β1 and reconciles experimental discrepancies that have been reported for this multifunctional cytokine.

scholarly journals Activation of the JNK/MAPK Signaling Pathway by TGF-β1 Enhances Neonatal Fc Receptor Expression and IgG Transcytosis

2021 ◽  
Vol 9 (4) ◽  
pp. 879
Author(s):  
Shaoju Qian ◽  
Chenxi Li ◽  
Xi Liu ◽  
Xiangchao Jia ◽  
Yuncai Xiao ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Cell Types ◽  
Transforming Growth Factor Β1 ◽  
Mapk Signaling ◽  
Fc Receptor ◽  
Receptor Expression ◽  
Mitogen Activated Protein Kinase ◽  
Luciferase Reporter ◽  
Neonatal Fc Receptor ◽  
Tgf Β1

The neonatal Fc receptor (FcRn) transports maternal immunoglobulin G (IgG) to the foetus or newborn and protects the IgG from degradation. FcRn is expressed in several porcine tissues and cell types and its expression levels are regulated by immune and inflammatory events. IPEC-J2 cells are porcine intestinal columnar epithelial cells that were isolated from neonatal piglet mid-jejunum. We hypothesized that transforming growth factor β1 (TGF-β1) upregulated pFcRn expression in IPEC-J2 cells. To test this hypothesis, we treated IPEC-J2 cells with TGF-β1 and demonstrated that porcine FcRn (pFcRn) expression was significantly increased. SP600125, a specific mitogen-activated protein kinase (MAPK) inhibitor, reduced TGF-β1-induced pFcRn expression in IPEC-J2 cells. We performed luciferase reporter assays and showed that the c-JUN sensitive region of the pFcRn promoter gene was located between positions −1215 and −140. The c-JUN sequence, in combination with the pFcRn promoter, regulated luciferase reporter activity in response to TGF-β1 stimulation. Chromatin immunoprecipitation confirmed that there were three c-JUN binding sites in the pFcRn promoter. Furthermore, in addition to increased pFcRn expression, TGF-β1 also enhanced IgG transcytosis in IPEC-J2 cells. In summary, our data showed that the modulation of JNK/MAPK signaling by TGF-β1 was sufficient to upregulate pFcRn expression.

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