scholarly journals MiR-216a-5p-containing exosomes suppress rTp17-induced inflammatory response by targeting TLR4

2019 ◽  
Vol 39 (8) ◽  
Author(s):  
Rui-Rui Peng ◽  
Shu-Xian Shang ◽  
Li-Shi Zhao ◽  
Fu-Quan Long
Keyword(s):  
Endothelial Cells ◽  
Inflammatory Response ◽  
Therapeutic Target ◽  
Molecular Mechanisms ◽  
Treponema Pallidum ◽  
Worldwide Distribution ◽  
Tnf Α ◽  
Healthy Control ◽  
Myd88 Signaling

Abstract Syphilis caused by Treponema pallidum (T. pallidum) infection is accompanied by inflammatory injury of tissue, and has a worldwide distribution and increasing incidence over the past decade. Tp17 has been reported to be a strong membrane immunogen, and was initially observed to play a role in inflammation during syphilis, reacting intensely with human syphilitic sera. We therefore used recombinant Tp17 (rTp17) as a stimulator in our study. Increasing evidence has demonstrated that microRNA (miRNA)-containing exosomes have emerged as a potential effective therapeutic target for many diseases. However, the biological functions and molecular mechanisms of miR-216a-5p in syphilis pathogenesis remain unknown. Our study first identified dramatically decreased miR-216a-5p in plasma of syphilis patients compared with the healthy control, which was negatively correlated with the expression of inflammatory cytokines, including IL-1β, IL-6, and TNF-α. Moreover, endothelial cells treated with miR-216a-5p-containing exosomes significantly attenuated the rTp17-induced inflammatory response. More importantly, we identified that miR-216a-5p could bind to the 3′-untranslated region (UTR) of Toll-like receptor (TLR) 4 (TLR4), and overexpression of TLR4 largely rescued the miR-216a-5p-mediated suppression of rTp17-induced inflammatory cytokine production and the TLR4-MYD88 signaling pathway. Thus, our results reveal a novel role of miR-216a-5p-containing exosomes in endothelial cells, implying a potential therapeutic target for inflammation in syphilis patients.

scholarly journals Supervillin contributes to LPS-induced inflammatory response in THP-1 cell-derived macrophages

2021 ◽  
Author(s):  
Jun Zhou ◽  
Yuhui Que ◽  
Lihua Pan ◽  
Xu Li ◽  
Chao Zhu ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Protein Expression ◽  
Mrna Expression ◽  
Inflammatory Cytokines ◽  
Molecular Mechanisms ◽  
Actin Binding ◽  
Tnf Α ◽  
Mrna And Protein Expression ◽  
Underlying Mechanisms

Abstract Supervillin (SVIL), the largest member of villin/gelsolin family, is an actin-binding and membrane-associated protein, that can also be localized to the nucleus. It has been reported that the mRNA expression of SVIL in neutrophils could be increased by lipopolysaccharide (LPS), but the underlying mechanisms remain unknown. Moreover, SVIL was also observed to be involved in the regulation of macrophages’ movement. However, it is not clear whether SVIL is involved in the LPS-induced inflammatory response in macrophages. This work was to investigate the underlying molecular mechanisms of LPS regulating SVIL expression in macrophages and hence the possible role of SVIL in LPS-induced inflammation. Our data showed that in THP-1-derived macrophages, LPS stimulation significantly increased SVIL mRNA and protein expression. Inhibition of TLR4 by Resatorvid (Res) completely reversed the expression of SVIL and inflammatory cytokines (IL-6, IL-1β and TNF-α) induced by LPS. Additionally, ERK1/2 and NF-κB inhibitors (U0126 and BAY) significantly reduced SVIL and IL-6, IL-1β & TNF-α expression. Furthermore, down-regulation of SVIL by SVIL-specific shRNA significantly attenuated the expression of IL-6, IL-1β & TNF-α induced by LPS. Taken together, as a downstream molecule of TLR4/NF-κB and ERK1/2, SVIL was involved in the inflammatory response of LPS-induced elevated IL-6, IL-1β and TNF-α in macrophages.

scholarly journals Expression and role of ABIN1 in sepsis: In vitro and in vivo studies

Open Medicine ◽  
2020 ◽  
Vol 16 (1) ◽  
pp. 033-040
Author(s):  
Haolan Li ◽  
Aichen Sun ◽  
Taocheng Meng ◽  
Yan Zhu
Keyword(s):  
Inflammatory Response ◽  
Molecular Mechanisms ◽  
Organ Injury ◽  
In Vivo Studies ◽  
Inflammatory Factors ◽  
Septic Mouse ◽  
Raw264.7 Macrophages ◽  
Tnf Α

AbstractIn this research, we attempted to explain the effect and the related molecular mechanisms of ABIN1 in lipopolysaccharide (LPS)-induced septic mice or RAW264.7 macrophages. LPS was adopted to treat RAW264.7 macrophages for 4 h, and the levels of inflammatory factors were assessed by ELISA. Besides, ABIN1 expression was measured by quantitative reverse transcription polymerase chain reaction. Apparently, LPS enhanced immunoreaction, suggested by increased expression of IL-1β, tumor necrosis factor (TNF)-α, and IL-6. ABIN1 levels were obviously reduced compared to the control. Furthermore, we evaluated the roles of ABIN1-plasmid in immunoreaction and nuclear factor-κB (NF-κB) pathway. We found that ABIN1-plasmid significantly reduced the expression of IL-1β, TNF-α, and IL-6 in LPS-treated cells and inhibited NF-κB pathway activation. Meanwhile, a septic mouse mode was conducted to validate the role of ABIN1 in inflammatory response and organ damage in vivo. These data suggested that ABIN1-plasmid significantly inhibited the secretion of inflammatory cytokines and Cr, BUN, AST, and ALT levels in the serum of LPS-stimulated mice compared to LPS + control-plasmid group, reflecting the relieved inflammation and organ injury. In summary, the present findings indicated that ABIN1 alleviated sepsis by repressing inflammatory response through NF-κB signaling pathway, emphasizing the potential value of ABIN1 as therapeutic strategy for sepsis.

scholarly journals Effect of Cyclic Stretch on Vascular Endothelial Cells and Abdominal Aortic Aneurysm (AAA): Role in the Inflammatory Response

2019 ◽  
Vol 20 (2) ◽  
pp. 287 ◽  
Author(s):  
Martina Ramella ◽  
Giulia Bertozzi ◽  
Luca Fusaro ◽  
Maria Talmon ◽  
Marcello Manfredi ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Inflammatory Response ◽  
Mechanical Stress ◽  
Mechanical Stimulation ◽  
Cyclic Stretch ◽  
Abdominal Aortic ◽  
Tnf Α

Abdominal aortic aneurysm (AAA) is a focal dilatation of the aorta, caused by both genetic and environmental factors. Although vascular endothelium plays a key role in AAA progression, the biological mechanisms underlying the mechanical stress involvement are only partially understood. In this study, we developed an in vitro model to characterize the role of mechanical stress as a potential trigger of endothelial deregulation in terms of inflammatory response bridging between endothelial cells (ECs), inflammatory cells, and matrix remodeling. In AAA patients, data revealed different degrees of calcification, inversely correlated with wall stretching and also with inflammation and extracellular matrix degradation. In order to study the role of mechanical stimulation, endothelial cell line (EA.hy926) has been cultured in healthy (10% strain) and pathological (5% strain) dynamic conditions using a bioreactor. In presence of tumor necrosis factor alpha (TNF-α), high levels of matrix metalloproteinase-9 (MMP-9) expression and inflammation are obtained, while mechanical stimulation significantly counteracts the TNF-α effects. Moreover, physiological deformation also plays a significant role in the control of the oxidative stress. Overall our findings indicate that, due to wall calcification, in AAA there is a significant change in terms of decreased wall stretching.

Regulation of microRNAs in Inflammation-Associated Colorectal Cancer: A Mechanistic Approach

2020 ◽  
Vol 20 ◽  
Author(s):  
Sridhar Muthusami ◽  
Ilangovan Ramachandran ◽  
Sneha Krishnamoorthy ◽  
Yuvaraj Sambandam ◽  
Satish Ramalingam ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Molecular Mechanisms ◽  
Colorectal Carcinogenesis ◽  
Model Systems ◽  
Necrosis Factor Alpha ◽  
Multi Stage ◽  
Mechanistic Approach ◽  
Tnf Α ◽  
Factor Alpha

: The development of colorectal cancer (CRC) is a multi-stage process. The inflammation of the colon as in inflammatory bowel disease (IBD) such as ulcerative colitis (UC) or Crohn’s disease (CD) is often regarded as the initial trigger for the development of CRC. Many cytokines such as tumor necrosis factor alpha (TNF-α) and several interleukins (ILs) are known to exert proinflammatory actions, and inflammation initiates or promotes tumorigenesis of various cancers, including CRC through differential regulation of microRNAs (miRNAs/miRs). miRNAs can be oncogenic miRNAs (oncomiRs) or anti-oncomiRs/tumor suppressor miRNAs, and they play key roles during colorectal carcinogenesis. However, the functions and molecular mechanisms of regulation of miRNAs involved in inflammation-associated CRC are still anecdotal and largely unknown. Consolidating the published results and offering perspective solutions to circumvent CRC, the current review is focused on the role of miRNAs and their regulation in the development of CRC. We have also discussed the model systems adapted by researchers to delineate the role of miRNAs in inflammation-associated CRC.

scholarly journals Let-7a-5p regulates the inflammatory response in chronic rhinosinusitis with nasal polyps

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Jianwei Zhang ◽  
Lei Han ◽  
Feng Chen
Keyword(s):  
Inflammatory Response ◽  
Chronic Rhinosinusitis ◽  
Nasal Polyps ◽  
Mapk Pathway ◽  
Inhibitory Effect ◽  
Luciferase Reporter ◽  
Western Blot Assay ◽  
Protein Levels ◽  
Tnf Α

Abstract Background Let-7a-5p is demonstrated to be a tumor inhibitor in nasopharyngeal carcinoma. However, the role of let-7a-5p in chronic rhinosinusitis with nasal polyps (CRSwNP) has not been reported. This study is designed to determine the pattern of expression and role of let-7a-5p in CRSwNP. Methods The expression level of let-7a-5p, TNF-α, IL-1β, and IL-6 in CRSwNP tissues and cells were detected by RT-qPCR. Western blot assay was carried out to measure the protein expression of the Ras-MAPK pathway. Dual luciferase reporter assay and RNA pull-down assay were used to explore the relationship between let-7a-5p and IL-6. Results Let-7a-5p was significantly downregulated in CRSwNP tissues and cells. Moreover, the mRNA expression of TNF-α, IL-1β and IL-6 was increased in CRSwNP tissues, while let-7a-5p mimic inhibited the expression of TNF-α, IL-1β and IL-6. Besides that, let-7a-5p was negatively correlated with TNF-α, IL-1β and IL-6 in CRSwNP tissues. In our study, IL-6 was found to be a target gene of let-7a-5p. Additionally, let-7-5p mimic obviously reduced the protein levels of Ras, p-Raf1, p-MEK1 and p-ERK1/2, while IL-6 overexpression destroyed the inhibitory effect of let-7a-5p on the Ras-MAPK pathway in CRSwNP. Conclusion We demonstrated that let-7a-5p/IL-6 interaction regulated the inflammatory response through the Ras-MAPK pathway in CRSwNP.

scholarly journals TNF-α-Induced YAP/TAZ Activity Mediates Leukocyte-Endothelial Adhesion by Regulating VCAM1 Expression in Endothelial Cells

2018 ◽  
Vol 19 (11) ◽  
pp. 3428 ◽  
Author(s):  
Hyun-Jung Choi ◽  
Na-Eun Kim ◽  
Byeong Kim ◽  
Miran Seo ◽  
Ji Heo
Keyword(s):  
Endothelial Cells ◽  
Rho Gtpases ◽  
Leukocyte Adhesion ◽  
Hippo Pathway ◽  
Specific Inhibitor ◽  
Vascular Diseases ◽  
Adhesive Properties ◽  
Sprouting Angiogenesis ◽  
Tnf Α

YAP/TAZ, a transcriptional co-activator of Hippo pathway, has emerged as a central player in vessel homeostasis such as sprouting angiogenesis and vascular barrier stabilization, during development. However, the role of YAP/TAZ in pathological angiogenesis remains unclear. Here, we demonstrated that YAP/TAZ is a critical mediator in leukocyte-endothelial adhesion induced by the vascular inflammatory cytokine TNF-α. YAP/TAZ was dephosphorylated, translocated from the cytosol to the nucleus, and activated by TNF-α in endothelial cells. A specific inhibitor of Rho GTPases suppressed the TNF-α-induced dephosphorylation of YAP. Knockdown of YAP/TAZ using siRNA significantly reduced the expression of the leukocyte adhesion molecule VCAM1 induced by TNF-α. The adhesion of monocytes to endothelial cells was also markedly reduced by YAP/TAZ silencing. However, knockdown of YAP/TAZ did not affect TNF-α-induced NF-κB signaling. Overall, these results suggest that YAP/TAZ plays critical roles in regulating TNF-α-induced endothelial cell adhesive properties without affecting the NF-κB pathway, and implicate YAP/TAZ as a potential therapeutic target for treating inflammatory vascular diseases.

scholarly journals Clinical significance of miR-129-5p in patients with neonatal sepsis and its regulatory role in the LPS-induced inflammatory response

2020 ◽  
Author(s):  
Meng Li ◽  
Xiaoyang Huang ◽  
Qingcui Zhuo ◽  
Jinghui Zhang ◽  
Xiuli Ju
Keyword(s):  
Inflammatory Response ◽  
Clinical Significance ◽  
Neonatal Sepsis ◽  
Close Association ◽  
Disease Diagnosis ◽  
Diagnostic Value ◽  
Regulatory Role ◽  
Value Analysis ◽  
Tnf Α

Neonatal sepsis (NS) occurs in neonates within 28 days, especially preterm infants. The dysregulation of miRNAs is widely detected in NS. The study investigated the expression changes and clinical significance of miR-129-5p in NS patients and further explored the regulatory role of miR-129-5p in the LPS-induced inflammatory response in monocytes. A total of 75 neonates with NS and 84 neonates without NS were recruited. qRT-PCR was used for the measurement of miR-129-5p expression. The receiver operating characteristic (ROC) curve was constructed for diagnostic value analysis. ELISA was used to detect the concentration of inflammatory cytokines. Monocytes were isolated from the blood of neonates to investigate the role of miR-129-5p in the LPS-induced inflammatory response in vitro. miR-129-5p was low expressed in the serum of NS cases compared with controls. Serum miR-129-5p had a diagnostic value for NS with a sensitivity of 82.7% and specificity of 79.8%. There was close association for serum miR-129-5p with TNF-α (r = -0.652, p < 0.001) and IL-8 (r = -0.700, p < 0.001) levels in NS patients. Overexpression of miR-129-5p reversed the increasing trend of TNF-α and IL-8 induced by LPS, whereas miR-129-5p downregulation aggravated the increase of TNF-α and IL-8 induced by LPS in monocytes. MiR-129-5p was downregulated in the serum of NS patients, and it might be a promising biomarker for disease diagnosis. Overexpression of miR-129-5p alleviated the inflammatory response of NS.

scholarly journals Proinflammatory responses in SARS-CoV-2 infected and soluble spike glycoprotein S1 subunit activated human macrophages

2021 ◽  
Author(s):  
Kim Chiok ◽  
Kevin Hutchison ◽  
Lindsay Grace Miller ◽  
Santanu Bose ◽  
Tanya A Miura
Keyword(s):  
Virus Infection ◽  
Inflammatory Response ◽  
Virus Replication ◽  
Inflammatory Mediators ◽  
Inflammatory Responses ◽  
Activated Macrophages ◽  
Human Macrophages ◽  
Tnf Α ◽  
Proinflammatory Responses

Critically ill COVID-19 patients infected with SARS-CoV-2 display signs of generalized hyperinflammation. Macrophages trigger inflammation to eliminate pathogens and repair tissue, but this process can also lead to hyperinflammation and resulting exaggerated disease. The role of macrophages in dysregulated inflammation during SARS-CoV-2 infection is poorly understood. We used SARS-CoV-2 infected and glycosylated soluble SARS-CoV-2 Spike S1 subunit (S1) treated THP-1 human-derived macrophage-like cell line to clarify the role of macrophages in pro-inflammatory responses. Soluble S1 upregulated TNF-α and CXCL10 mRNAs, and induced secretion of TNF-α from THP-1 macrophages. While THP-1 macrophages did not support productive SARS-CoV-2 replication, virus infection resulted in upregulation of both TNF-α and CXCL10 genes. Our study shows that S1 is a key viral component inducing inflammatory response in macrophages, independently of virus replication. Thus, virus-infected or soluble S1-activated macrophages may become sources of pro-inflammatory mediators contributing to hyperinflammation in COVID-19 patients.

scholarly journals MiR-22-3p suppresses sepsis-induced acute kidney injury by targeting PTEN

2020 ◽  
Vol 40 (6) ◽  
Author(s):  
Xudong Wang ◽  
Yali Wang ◽  
Mingjian Kong ◽  
Jianping Yang
Keyword(s):  
Acute Kidney Injury ◽  
Inflammatory Response ◽  
Periodic Acid ◽  
Kidney Injury ◽  
Luciferase Reporter ◽  
Tunel Staining ◽  
Tnf Α

Abstract Background: Septic acute kidney injury is considered as a severe and frequent complication that occurs during sepsis. The present study was performed to understand the role of miR-22-3p and its underlying mechanism in sepsis-induced acute kidney injury. Methods: Rats were injected with adenovirus carrying miR-22-3p or miR-NC in the caudal vein before cecal ligation. Meanwhile, HK-2 cells were transfected with the above adenovirus following LPS stimulation. We measured the markers of renal injury (blood urea nitrogen (BUN), serum creatinine (SCR)). Histological changes in kidney tissues were examined by hematoxylin and eosin (H&E), Masson staining, periodic acid Schiff staining and TUNEL staining. The levels of IL-1β, IL-6, TNF-α and NO were determined by ELISA assay. Using TargetScan prediction and luciferase reporter assay, we predicted and validated the association between PTEN and miR-22-3p. Results: Our data showed that miR-22-3p was significantly down-regulated in a rat model of sepsis-induced acute kidney injury, in vivo and LPS-induced sepsis model in HK-2 cells, in vitro. Overexpression of miR-22-3p remarkably suppressed the inflammatory response and apoptosis via down-regulating HMGB1, p-p65, TLR4 and pro-inflammatory factors (IL-1β, IL-6, TNF-α and NO), both in vivo and in vitro. Moreover, PTEN was identified as a target of miR-22-3p. Furthermore, PTEN knockdown augmented, while overexpression reversed the suppressive role of miR-22-3p in LPS-induced inflammatory response. Conclusions: Our results showed that miR-22-3p induced protective role in sepsis-induced acute kidney injury may rely on the repression of PTEN.

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