scholarly journals Notch Signaling Mediates TNF-α-Induced IL-6 Production in Cultured Fibroblast-Like Synoviocytes from Rheumatoid Arthritis

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Zhijun Jiao ◽  
Wenhong Wang ◽  
Jie Ma ◽  
Shengjun Wang ◽  
Zhaoliang Su ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Notch Signaling ◽  
Target Gene ◽  
Cytokine Production ◽  
Notch Pathway ◽  
Mrna Levels ◽  
Secretase Inhibitor ◽  
Tnf Α ◽  
Functional Involvement ◽  
Fibroblast Like Synoviocytes

It has been reported that Notch family proteins are expressed in synovium tissue and involved in the proliferation of synoviocyte from rheumatoid arthritis (RA). The aim of this paper was to investigate whether Notch signaling mediated TNF-α-induced cytokine production of cultured fibroblast-like synoviocytes (FLSs) from RA. Exposure of RA FLSs to TNF-α(10 ng/ml) led to increase of Hes-1, a target gene of Notch signaling, and a marked upregulation of Notch 2, Delta-like 1, and Delta-like 3 mRNA levels. Blockage of Notch signaling by aγ-secretase inhibitor (DAPT) inhibited IL-6 secretion of RA FLSs in response to TNF-αwhile treatment with recombinant fusion protein of Notch ligand Delta-like 1 promoted such response. TNF-αstimulation also induced IL-6 secretion in OA FLSs; however, the Hes-1 level remained unaffected. Our data confirm the functional involvement of Notch pathway in the pathophysiology of RA FLSs which may provide a new target for RA therapy.

scholarly journals Evaluation of TAK-242 (Resatorvid) Effects on Inflammatory Status of Fibroblast-like Synoviocytes in Rheumatoid Arthritis and Trauma Patients

2021 ◽  
Author(s):  
Jafar Karami ◽  
Elham Farhadi ◽  
Ali-Akbar Delbandi ◽  
Mehdi Shekarabi ◽  
Mohammad Naghi Tahmasebi ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Signaling Pathway ◽  
Inflammatory Responses ◽  
Nuclear Factor Κb ◽  
Trauma Patients ◽  
Mrna Levels ◽  
Control Groups ◽  
Inflammatory Status ◽  
Tnf Α ◽  
Fibroblast Like Synoviocytes

Fibroblast-like synoviocytes (FLSs) produce lots of inflammatory molecules that trigger immune responses and intensification the inflammation and thereby play important roles in Rheumatoid Arthritis )RA( pathogenesis. Due to the important roles of toll-like receptor 4 (TLR4) in cytokine production and inflammation, we aimed to evaluate the effects of TAK-242 (Resatorvid) on interleukin (IL)1-β, IL-6, TNF-α, and TLR4 expression and two important proteins of nuclear factor-κB (NF-κB) signaling pathway (Ikβα and pIkβα) in RA and trauma FLSs. FLSs were isolated from synovial tissues of trauma (n=10) and RA (n=10) patients and cultured in Dulbecco's Modified Eagle Medium (DMEM). 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide (MTT) was performed to evaluate the cytotoxicity effects of TAK-242 on the RA FLSs. Real-time PCR was performed to measure the expression level of IL1-β, IL-6, TNF-α, and TLR4 genes in Lipopolysaccharide (LPS) and TAK-242 treated FLSs. Furthermore, the treated FLSs were evaluated for protein levels of Ikβα and pIkβα by western blot. The baseline expression of IL1-β, IL-6, TNF-α, and TLR4 showed no significant differences between healthy and RA FLSs. LPS stimulated FLSs significantly increased mRNA levels of IL-1β, IL-6, TNF-α, and TLR4 genes in both the healthy and RA FLSs compared with that of their control groups, and pretreatment with TAK-242 reversed the effect. Furthermore, LPS-stimulated FLSs significantly increased the level of pIkβα in both the healthy and RA FLSs compared with that of their control groups, and pretreatment with TAK-242 reversed the effect. We provide the data that TAK-242 through inhibiting the NF-κB signaling pathway may modulate TLR4-mediated inflammatory responses and could be considered as a potential therapeutic agent for RA patients.

scholarly journals LAIR-1 shedding from human fibroblast-like synoviocytes in rheumatoid arthritis following TNF-α stimulation

2018 ◽  
Vol 192 (2) ◽  
pp. 193-205 ◽  
Author(s):  
Y. Zhang ◽  
S. Wang ◽  
H. Dong ◽  
X. Yi ◽  
J. Zhang ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Human Fibroblast ◽  
Tnf Α ◽  
Fibroblast Like Synoviocytes

scholarly journals Propofol Alleviates Neuropathic Pain in CCI Rat Model via the miR-140-3p/JAG1/Notch Signaling Pathway

2021 ◽  
Author(s):  
Fang Cheng ◽  
Wei Qin ◽  
Ai-xing Yang ◽  
Feng-feng Yan ◽  
Yu chen ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Notch Signaling ◽  
Signaling Pathway ◽  
Notch Pathway ◽  
Thermal Hyperalgesia ◽  
Underlying Mechanism ◽  
Notch Signaling Pathway ◽  
Mechanical Threshold ◽  
Tnf Α ◽  
Related Proteins

Abstract As a renowned anesthetic, propofol exerts excellent analgesic function in nerve injury. However, the underlying mechanism of propofol on neuropathic pain (NP) remains unknown. The research aims to analyze propofol’s analgesia mechanism to alleviate NP in CCI rats. The chronic constriction injury (CCI) of sciatic nerve was used to established NP rat models. CCI rats were treated with propofol and its paw withdrawal mechanical threshold (PMWT) and paw withdraw thermal latency (PWTL) were measured. The expressions of TNF-α, IL-1β and IL-10 were detected. CCI rats with propofol treatment were injected with antagomiR-140-3p. After the targeting relationship between miR-140-3p and JAG1 was checked, JAG1 expression was detected. Propofol-treated CCI rats were further injected with Ad-JAG1. Finally, the levels of JAG1 and Notch pathway-related proteins were detected. As a result, propofol could alleviate NP, including thermal hyperalgesia and mechanical pain threshold, and ameliorate neuroinflammation. Mechanically, propofol enhanced the level of miR-140-3p in CCI rats. JAG1 was a direct target of miR-140-3p. The downregulation of miR-140-3p or upregulation of JAG1 could reduce the protective effect of propofol against NP. Propofol inhibited activation of Notch signaling via miR-140-3p/JAG1. Overall, Propofol could inhibit the neuroinflammation and Notch signaling pathway via miR-140-3p/JAG1 to alleviate NP.

scholarly journals The effect of nicotinamide adenine dinucleotide phosphate oxidase 4 on migration and invasion of fibroblast-like synoviocytes in rheumatoid arthritis

2020 ◽  
Author(s):  
Ha-Reum Lee ◽  
Su-Jin Yoo ◽  
Jinhyun Kim ◽  
In Seol Yoo ◽  
Chan Keol Park ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Cell Migration ◽  
Adhesion Molecule ◽  
Nicotinamide Adenine Dinucleotide ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Nicotinamide Adenine ◽  
Migration And Invasion ◽  
Interleukin 17 ◽  
Tnf Α ◽  
Fibroblast Like Synoviocytes

Abstract Background: Reactive oxygen species (ROS) regulate the migration and invasion of fibroblast-like synoviocytes (FLS), which are key effector cells in rheumatoid arthritis (RA) pathogenesis. Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) induces ROS generation and consequently, enhances cell migration. Despite the important interrelationship between RA, FLS, and ROS, the effect of NOX4 on RA pathogenesis remains unclear. Methods: FLS isolated from RA (n=5) and osteoarthritis (OA, n=5) patients were stimulated with recombinant interleukin 17 (IL-17; 10 ng/ml) and tumor necrosis factor alpha (TNF-α; 10 ng/ml) for 1 h. Cell migration, invasion, adhesion molecule expression, vascular endothelial growth factor (VEGF) secretion, and ROS expression were examined. The mRNA and protein levels of NOX4 were analyzed by RT-qPCR and western blotting, respectively. The NOX4 inhibitor GLX351322 and NOX4 siRNA were used to inhibit NOX4 to probe the effect of NOX4 on these cellular processes. Results: Migration of RA FLS was increased 2.48-fold after stimulation with IL-17 and TNF-α, while no difference was observed for OA FLS. ROS expression increased in parallel with invasiveness of FLS following cytokine stimulation. When the expression of NOX was examined, NOX4 was significantly increased by 9.73-fold in RA FLS compared to unstimulated FLS. Following NOX4 inhibition, cytokine-induced vascular cell adhesion molecule 1 (VCAM1), VEGF, and migration and invasion capacity of RA FLS were markedly decreased to unstimulated levels. Conclusion: NOX4 is a key contributor to cytokine-enhanced migration and invasion via modulation of ROS, VCAM1, and VEGF in RA FLS.

scholarly journals Dysregulated Notch Signaling in the Airway Epithelium of Children with Wheeze

2021 ◽  
Vol 11 (12) ◽  
pp. 1323
Author(s):  
Thomas Iosifidis ◽  
Erika N. Sutanto ◽  
Samuel T. Montgomery ◽  
Patricia Agudelo-Romero ◽  
Kevin Looi ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Notch Signaling ◽  
Airway Epithelium ◽  
Wound Repair ◽  
Notch Pathway ◽  
Airway Epithelial Cells ◽  
Mrna Levels ◽  
Airway Epithelial ◽  
Closure Rate

The airway epithelium of children with wheeze is characterized by defective repair that contributes to disease pathobiology. Dysregulation of developmental processes controlled by Notch has been identified in chronic asthma. However, its role in airway epithelial cells of young children with wheeze, particularly during repair, is yet to be determined. We hypothesized that Notch is dysregulated in primary airway epithelial cells (pAEC) of children with wheeze contributing to defective repair. This study investigated transcriptional and protein expression and function of Notch in pAEC isolated from children with and without wheeze. Primary AEC of children with and without wheeze were found to express all known Notch receptors and ligands, although pAEC from children with wheeze expressed significantly lower NOTCH2 (10-fold, p = 0.004) and higher JAG1 (3.5-fold, p = 0.002) mRNA levels. These dysregulations were maintained in vitro and cultures from children with wheeze displayed altered kinetics of both NOTCH2 and JAG1 expression during repair. Following Notch signaling inhibition, pAEC from children without wheeze failed to repair (wound closure rate of 76.9 ± 3.2%). Overexpression of NOTCH2 in pAEC from children with wheeze failed to rescue epithelial repair following wounding. This study illustrates the involvement of the Notch pathway in airway epithelial wound repair in health and disease, where its dysregulation may contribute to asthma development.

Sign in / Sign up

Export Citation Format

Share Document