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.

Synergistic induction of nuclear factor-κB by transforming growth factor-β and tumour necrosis factor-α is mediated by protein kinase A-dependent RelA acetylation

2008 ◽  
Vol 417 (2) ◽  
pp. 583-591 ◽  
Author(s):  
Hajime Ishinaga ◽  
Hirofumi Jono ◽  
Jae Hyang Lim ◽  
Kensei Komatsu ◽  
Xiangbin Xu ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Transforming Growth Factor Β ◽  
Nuclear Factor Κb ◽  
Binding Activity ◽  
Dna Binding Activity ◽  
Tnf Α ◽  
Factor Α ◽  
Tgf Β1 ◽  
Necrosis Factor

The TGF-β (transforming growth factor-β) pathway represents an important signalling pathway involved in regulating diverse biological processes, including cell proliferation, differentiation and inflammation. Despite the critical role for TGF-β in inflammatory responses, its role in regulating NF-κB (nuclear factor-κB)-dependent inflammatory responses still remains unknown. In the present study we show that TGF-β1 synergizes with proinflammatory cytokine TNF-α (tumour necrosis factor-α) to induce NF-κB activation and the resultant inflammatory response in vitro and in vivo. TGF-β1 synergistically enhances TNF-α-induced NF-κB DNA binding activity via induction of RelA acetylation. Moreover, synergistic enhancement of TNF-α-induced RelA acetylation and DNA-binding activity by TGF-β1 is mediated by PKA (protein kinase A). Thus the present study reveals a novel role for TGF-β in inflammatory responses and provides new insight into the regulation of NF-κB by TGF-β signalling.

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.

Regulation of Murine Protein C Gene Expression In Vivo: Effects of Tumor Necrosis Factor-α, Interleukin-1, and Transforming Growth Factor-β

1999 ◽  
Vol 82 (10) ◽  
pp. 1297-1301 ◽  
Author(s):  
Takayoshi Shimokawa ◽  
Tetsuhito Kojima ◽  
David Loskutoff ◽  
Hidehiko Saito ◽  
Koji Yamamoto
Keyword(s):  
Growth Factor ◽  
Protein C ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Transforming Growth Factor ◽  
Interleukin 1 ◽  
Transforming Growth Factor Β ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

SummaryProtein C is a precursor of the anticoagulant serine protease, activated protein C, which inhibits coagulation factors Va and VIIIa. Although the liver appears to be the primary site of protein C synthesis, we previously demonstrated that the kidney and male reproductive organs also expressed abundant protein C mRNA in the mouse. In the present study, we further investigated the effects of tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and transforming growth factor-β (TGF-β) on the expression of protein C mRNA in the principal producing organs, i.e., the liver, kidney, and testis. Both quantitative reverse transcription-PCR assay and in situ hybridization analysis revealed that TNF-α decreased protein C mRNA expression in the liver, kidney, and testis. IL-1 also down-regulated protein C mRNA expression in the liver and testis, but not in the kidney. In contrast, TGF-β unchanged the expression level of protein C mRNA in these three organs. These observations suggest that TNF-α and IL-1 may contribute to an increase in the procoagulant potential by down-regulation of protein C synthesis in the tissues during inflammatory processes.

scholarly journals Demystifying Excess Immune Response in COVID-19 to Reposition an Orphan Drug for Down-Regulation of NF-κB: A Systematic Review

Viruses ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 378
Author(s):  
Apparao Peddapalli ◽  
Manish Gehani ◽  
Arunasree M. Kalle ◽  
Siva R. Peddapalli ◽  
Angela E. Peter ◽  
...  
Keyword(s):  
Immune Response ◽  
Nuclear Translocation ◽  
Nuclear Factor Κb ◽  
Common Pathway ◽  
Downstream Effectors ◽  
Tnf Α ◽  
Normal Human ◽  
Factor Α ◽  
Necrosis Factor ◽  
Pro Inflammatory Cytokines

The immunological findings from autopsies, biopsies, and various studies in COVID-19 patients show that the major cause of morbidity and mortality in COVID-19 is excess immune response resulting in hyper-inflammation. With the objective to review various mechanisms of excess immune response in adult COVID-19 patients, Pubmed was searched for free full articles not related to therapeutics or co-morbid sub-groups, published in English until 27 October 2020, irrespective of type of article, country, or region. Joanna Briggs Institute’s design-specific checklists were used to assess the risk of bias. Out of 122 records screened for eligibility, 42 articles were included in the final review. The review found that eventually, most mechanisms result in cytokine excess and up-regulation of Nuclear Factor-κB (NF-κB) signaling as a common pathway of excess immune response. Molecules blocking NF-κB or targeting downstream effectors like Tumour Necrosis Factor α (TNFα) are either undergoing clinical trials or lack specificity and cause unwanted side effects. Neutralization of upstream histamine by histamine-conjugated normal human immunoglobulin has been demonstrated to inhibit the nuclear translocation of NF-κB, thereby preventing the release of pro-inflammatory cytokines Interleukin (IL) 1β, TNF-α, and IL-6 and IL-10 in a safer manner. The authors recommend repositioning it in COVID-19.

scholarly journals Evaluation of Interleukin-1α, Interleukin-10, Tumor Necrosis Factor-α and transforming Growth Factor-β in the Serum of Patients with Pemphigus Vulgaris

2014 ◽  
Vol 15 (6) ◽  
pp. 746-749 ◽  
Author(s):  
Faezeh Khozeimeh ◽  
Omid Savabi ◽  
Masih Esnaashari
Keyword(s):  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Transforming Growth Factor ◽  
Pemphigus Vulgaris ◽  
Transforming Growth Factor Β ◽  
Interleukin 10 ◽  
Tnf Α ◽  
Interleukin 1Α ◽  
Factor Α ◽  
Necrosis Factor

ABSTRACT Pemphigus is an autoimmune blistering disease characterized by a loss of cell adhesion result in acantholysis. Genetic factors and immunologic factors such as cytokines particularly IL-1α, IL-10, TNF-α, and TGF-β may counterpart to developing of Pemphigus. The aim of this study was to evaluate. The concentration of IL-1α, IL-10, TNF-α, TGF-α in serum of pemphigus vulgaris (PV) patients and normal individuals. Material and methods In this analytic and descriptive study 25 patients with pemphigus vulgaris (in active phase) and 25 healthy persons were examined. Serum samples of two groups were obtained and the level of IL-1α, IL-10, TNF-α and TGF-β were measured by ELISA technique. The data were analyzed statistically by independent T test (α = 0/05). Results All cytokines tested, showed higher concentration in patient's sera comparing to healthy control individuals. The level of IL-1α (p = 0.004), TNF-α (p = 0.008) and TGF-β (p = 0.009) were statistically different in two experimental groups, There was no significant difference in IL-10 level (p = 0.605). Conclusion Cytokines such as IL-1α, IL-10, TNF-α and TGF-β probably have a role in pathogenesis of PV. Further comprehensive studies are suggested to confirm these findings. How to cite this article Khozeimeh F, Savabi O, Esnaashari M. Evaluation of Interleukin-1α, Interleukin-10, Tumor Necrosis Factor-α and transforming Growth Factor-β in the Serum of Patients with Pemphigus Vulgaris. J Contemp Dent Pract 2014;15(6):746-749.

scholarly journals The Effect of Azadirachta indica leaves extract on Transforming Growth Factor-β and Tumor Necrosis Factor-α in a Plasmodium berghei infected Mice model

2021 ◽  
Vol 7 (1) ◽  
pp. 42
Author(s):  
Zainabur Rahmah
Keyword(s):  
Azadirachta Indica ◽  
Plasmodium Berghei ◽  
Tumor Necrosis ◽  
Leaf Extract ◽  
Tumor Necrosis Factor Α ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

Malaria is a health problem for the world's population and is predominantly located in tropical and subtropical areas. The three countries with the most malaria cases are India (58%), followed by Indonesia (20%), then Myanmar (16%). This study aims to determine the effect of neem leaf extract on increasing TGF-β expression and decreasing TNF-α expression in mice infected with Plasmodium berghei. In this study there were four groups, namely Treatment 1 (in Plasmodium berghei infection without therapy). Treatment 2 (in Plasmodium berghei infection and treated with Azadirachta indica leaf extract at a dose of 0.25 mg / g BW). Treatment 3 = (in Plasmodium berghei infection and therapy with Azadirachta indica leaves at a dose of 0.5 mg / g BW). Treatment 4 = (in Plasmodium berghei infection and treated with Azadirachta indica leaves at a dose of 1 mg / g BW). TGF-β examination by elisa method and TNF-α by immunohistochemistry. Data analysis using SEM (Structural Equation Modeling) The results of treatment 1 and 2 showed a decrease in plasma TGF-β expression (t = 1.13; tcount = 1.93; ≥ttabel = 1.96) and spleen (tcount = 1.53; tcount = 1.45; ≥ttabel = 1.96) but there was an increase in spleen TNF-α expression (tcount = 1.77; tcount = 1.00; ≥ttabel = 1.96). Groups 3 and 4 showed an increase in plasma TGF-β expression (tcount = 5.13; tcount = 2.42; ≥ttable = 1.96) and spleen (tcount = 2.00; tcount = 1.97; ≥ttabel = 1.96) but there was a decrease in spleen TNF-α expression (tcount = 2.03; tcount = 2.11; ≥ttabel = 1.96). Conclusion: Azadirachta indica leaf therapy can increase TGF-β expression and decrease TNF-α expression in the spleen. Keywords: Azadirachta indica ethanol extract, transforming growth factor- β, tumor necrosis factor-α

IL-10-inducible Bcl-3 negatively regulates LPS-induced TNF-α production in macrophages

Blood ◽  
2003 ◽  
Vol 102 (12) ◽  
pp. 4123-4129 ◽  
Author(s):  
Hirotaka Kuwata ◽  
Yasuyuki Watanabe ◽  
Hiroyuki Miyoshi ◽  
Masahiro Yamamoto ◽  
Tsuneyasu Kaisho ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Lentiviral Vector ◽  
Nuclear Factor Κb ◽  
Interleukin 10 ◽  
Nuclear Factor ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor ◽  
Inducible Gene

Abstract Interleukin-10 (IL-10) plays an important role in prevention of chronic inflammation in vivo. However, the molecular mechanism by which IL-10 exerts its anti-inflammatory response is poorly understood. Here, we performed a microarray analysis and identified Bcl-3 as an IL-10-inducible gene in macrophages. Lentiviral vector-mediated expression of Bcl-3 inhibited lipopolysaccharide (LPS)-induced production of tumor necrosis factor α (TNF-α), but not IL-6, in macrophages. In Bcl-3-transduced and IL-10-pretreated macrophages, LPS-induced nuclear translocation of nuclear factor κB (NF-κB) p65 was not impaired. However, DNA binding by NF-κB p50/p65 was profoundly inhibited. Nuclear localization of Bcl-3 was associated with inhibition of LPS-induced TNF-α production. Overexpression of Bcl-3 suppressed activation of the TNF-α promoter, but not the IL-6 promoter. Bcl-3 interacted with NF-κB p50 and was recruited to the TNF-α promoter, but not the IL-6 promoter, indicating that Bcl-3 facilitates p50-mediated inhibition of TNF-α expression. Furthermore, Bcl-3-deficient macrophages showed defective IL-10-mediated suppression of LPS induction of TNF-α, but not IL-6. These findings suggest that IL-10-induced Bcl-3 is required for suppression of TNF-α production in macrophages. (Blood. 2003; 102:4123-4129)

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