共查询到20条相似文献,搜索用时 11 毫秒
1.
Recent evidence supports a role of Toll-like receptor (TLR) signaling in the development of atherosclerotic lesions. It was
confirmed that the presence of functional TLR4 promotes a proinflammatory phenotype and proliferation of vascular smooth muscle
cells (VSMCs). Here we tested whether designed TLR4 small interfering RNAs (TLR4 siRNAs) is capable of inducing TLR4 deficient
and simultaneously regulating the expression of matrix metalloproteinase-9 (MMP-9) in human aortic smooth muscle cells (HASMCs).
Human aortic smooth muscle cells were obtained from Cascade Biologics (Portland, USA). The siRNAs used in this study were
chemically synthesized by Ambion, diluted in RNase free water at concentration of 2 μg/ml. The TLR4 siRNAs were complexed
with LipofectamineTM2000 in transfection buffer. After 30 min incubation at room temperature, the complexes were added to the cells. Subsequent
to 5 h incubation, cells were treated with 10 ng/ml LPS for 24 h. RT–PCR analysis was used to detect mRNA expression of GAPDH,
TLR4 and MMP-9; Western blot analysis was used to examine GAPDH, TLR4 and MMP-9 protein expression. It was shown that all
three designed TLR4 siRNAs inhibited the expression of TLR4 in HASMCs as compared to nontargeting siRNA. Notably, TLR4 siRNA-1
exhibited the strongest inhibition effect. Transfection of HASMCs with TLR4 siRNA-1 resulted in down-regulation of LPS-induced
expression of MMP-9. It was concluded that TLR4 siRNA-transfected HASMCs were capable for regulating the expression of MMP-9,
providing support for the rational design of siRNAs as atherosclerotic therapy. 相似文献
2.
The explosion of the toll-like receptors (TLRs) over the past decade has touched almost every field of mammalian biology and neuroscience is not an exception. The current advent of research papers examining the TLRs in the central nervous system (CNS) signifies that these receptors are not only involved in peripheral innate immunity but may also play a role in the development and regulation of CNS inflammation, neurodegeneration and brain trauma. This review addresses the potential role of TLRs in the brain and how they may be involved in various neuropathologies. 相似文献
3.
4.
Expression of functional chemokine receptors CXCR3 and CXCR4 on human melanoma cells 总被引:17,自引:0,他引:17
Robledo MM Bartolome RA Longo N Rodríguez-Frade JM Mellado M Longo I van Muijen GN Sánchez-Mateos P Teixidó J 《The Journal of biological chemistry》2001,276(48):45098-45105
Chemokines are secreted into the tumor microenvironment by tumor-infiltrating inflammatory cells as well as by tumor cells. Chemokine receptors mediate agonist-dependent cell responses, including migration and activation of several signaling pathways. In the present study we show that several human melanoma cell lines and melanoma cells on macroscopically infiltrated lymph nodes express the chemokine receptors CXCR3 and CXCR4. Using the highly invasive melanoma cell line BLM, we demonstrate that the chemokine Mig, a ligand for CXCR3, activates the small GTPases RhoA and Rac1, induces a reorganization of the actin cytoskeleton, and triggers cell chemotaxis and modulation of integrin VLA-5- and VLA-4-dependent cell adhesion to fibronectin. Furthermore, the chemokine SDF-1alpha, the ligand of CXCR4, triggered modulation of beta(1) integrin-dependent melanoma cell adhesion to fibronectin. Additionally, Mig and SDF-1alpha activated MAPKs p44/42 and p38 on melanoma cells. Expression of functional CXCR3 and CXCR4 receptors on melanoma cells indicates that they might contribute to cell motility during invasion as well as to regulation of cell proliferation and survival. 相似文献
5.
Basu S Fenton MJ 《American journal of physiology. Lung cellular and molecular physiology》2004,286(5):L887-L892
Toll-like receptor (TLR) proteins have been shown to play a pivotal role in both innate and adaptive immune responses in higher vertebrates. TLR proteins enable the host to recognize a large number of pathogen-associated molecular patterns such as bacterial lipopolysaccharides, viral RNA, CpG-containing DNA, and flagellin, among others. Engagement of TLR proteins leads to the upregulation of costimulatory molecules and proinflammatory cytokines, as well as reactive nitrogen and oxygen products. The role of TLR proteins in lung-associated pathologies such as airway hyperreactivity, allergic asthma, and tuberculosis is being intensively studied. This review summarizes many of the findings made to date on the roles of TLR proteins in a variety of lung diseases. Generally, TLR proteins serve a protective role in infectious diseases, such as tuberculosis. The progression of chronic inflammatory lung diseases, such as allergic asthma, can also be influenced by TLR-dependent responses. 相似文献
6.
Dandan Chen Fengxia Ma Shuxia Xu Shaoguang Yang Fang Chen Lijuan Rong Ying Chi Qinjun Zhao Shihong Lu Zhibo Han Aiming Pang Zhongchao Han 《Cytotherapy》2013,15(4):423-433
Background aimsToll-like receptors (TLRs) play an important role in innate and adaptive immunity by recognizing pathogen-associated molecular patterns (PAMPs).MethodsIn the present study, we investigated the expression and role of TLRs on human umbilical cord mesenchymal stromal cells (UC-MSCs). The proliferation, differentiation and immunoregulatory activity of UC-MSCs primed with or without TLR ligands were determined.ResultsAt the RNA level, the expression of TLR2, 4, 6 and 9 was relatively higher than that of other TLRs. However, TLR3 and TLR4 expression were relatively higher at the protein level. UC-MSCs expressed functional TLRs by nuclear factor-κB activation and cytokine expression assay. Poly-inosinic acid:cytidylic acid [Poly(I:C)] stimulation inhibited the proliferation of UC-MSCs, but the ligand of other TLRs had no significant effect. Poly(I:C) stimulation enhanced the adipogenic differentiation capability of UC-MSCs, but lipopolysaccharide inhibited the adipogenic differentiation. Poly(I:C) and CpG-oligonucleotide promoted the immunosuppressive potentiality of UC-MSCs, accompanied with the phosphorylation of interferon regulatory factor 3 (IRF3) and increased expression of indoleamine 2,3-dioxygenase and interferon β, whereas activation of other TLR ligands (synthetic analog fibroblast-stimulating lipopeptide-1 and lipopolysaccharide) failed to affect the immunoregulatory activity of UC-MSCs.ConclusionsTaken together, our data demonstrated that TLR activation influenced the function of UC-MSCs, which might have important implications in future efforts to explore the clinical potentials of UC-MSCs. 相似文献
7.
Nihon-Yanagi Y Terai K Murano T Matsumoto T Okazumi S 《Cancer immunology, immunotherapy : CII》2012,61(1):71-77
Background
Toll-like receptors (TLRs) play an important role in innate immunity by sensing a variety of pathogens and inducing acquired immunity. To test our hypothesis that dysregulation of innate immune responses acts to trigger carcinogenesis, we studied the expression of TLR2 and 4 in sporadic human colorectal cancer tissue. 相似文献8.
Valvular interstitial cells (VICs) are of mesenchymal origin and may differentiate into immune-like cells. This phenotypic plasticity is a key feature of aortic valve stenosis, but the role of epigenetic mechanisms has not previously been explored. Here we compared normal and calcified human aortic valve tissue. Calcified tissue exhibited decreased DNA-methylation in the promoter of the gene encoding the proinflammatory enzyme 5-lipoxygenase (5-LO), accompanied by increased 5-LO mRNA levels. Treatment of cultured VICs with the DNA methyltransferase inhibitor: 5-Aza-2'-deoxycytidine increased 5-LO mRNA levels and leukotriene production. These findings provide a first piece of evidence for epigenetic modifications of VICs in valvular heart disease. 相似文献
9.
Mohammadreza Yousefi Mina Mamipour Sadiye E. Sokullu Shahrooz Ghaderi Hassan Amini Reza Rahbarghazi 《Journal of cellular physiology》2019,234(11):19451-19463
Cardiac progenitor cells (CPCs) have the potential to differentiate into several cell lineages with the ability to restore in cardiac tissue. Multipotency and self-renewal activity are the crucial characteristics of CPCs. Also, CPCs have promising therapeutic roles in cardiac diseases such as valvular disease, thrombosis, atherosclerosis, congestive heart failure, and cardiac remodeling. Toll-like receptors (TLRs), as the main part of the innate immunity, have a key role in the development and differentiation of immune cells. Some reports are found regarding the effect of TLRs in the maturation of stem cells. This article tried to find the potential role of TLRs in the dynamics of CPCs. By showing possible crosstalk between the TLR signaling pathways and CPCs dynamics, we could achieve a better conception related to TLRs in the regeneration of cardiac tissue. 相似文献
10.
Chalajour F Treede H Ebrahimnejad A Lauke H Reichenspurner H Ergun S 《Experimental cell research》2004,298(2):2139-464
Here, we demonstrate the angiogenic response of valvular endothelial cells to aortic valve (AV) stenosis using a new ex vivo model of aortic leaflets. Histological analysis revealed neovascularization within the cusps of stenotic but not of non-stenotic aortic valves. Correspondingly, the number of capillary-like outgrowth in 3D collagen gel was significantly higher in stenotic than in non-stenotic valves. Capillary-like sprouting was developed significantly faster in stenotic than in non-stenotic valves. New capillary sprouts from stenotic aortic valves exhibited the endothelial cell markers CD31, CD34 and von-Willebrand factor (vWF) as well as carcinoembryonic antigen cell adhesion molecule-1 (CEACAM1), Tie-2 and angiogenesis inhibitor endostatin. Western blot analyses revealed a significant increase of CEACAM1 and endostatin in stenotic aortic valve tissue. Electron microscopic examinations demonstrate that these capillary-like tubes are formed by endothelial cells containing Weibel-Palade bodies. Remarkably, inter-endothelial junctions are established and basement membrane material is partially deposited on the basal side of the endothelial tubes. Our data demonstrate the capillary-like sprout formation from aortic valves and suggest a role of angiogenesis in the pathogenesis of aortic valve stenosis. These data provide new insights into the mechanisms of valvular disorders and open new perspectives for prevention and early treatment of calcified aortic stenosis. 相似文献
11.
H2AX: functional roles and potential applications 总被引:1,自引:0,他引:1
Jennifer S. Dickey Christophe E. Redon Asako J. Nakamura Brandon J. Baird Olga A. Sedelnikova William M. Bonner 《Chromosoma》2009,118(6):683-692
Upon DNA double-strand break (DSB) induction in mammals, the histone H2A variant, H2AX, becomes rapidly phosphorylated at
serine 139. This modified form, termed γ-H2AX, is easily identified with antibodies and serves as a sensitive indicator of
DNA DSB formation. This review focuses on the potential clinical applications of γ-H2AX detection in cancer and in response
to other cellular stresses. In addition, the role of H2AX in homeostasis and disease will be discussed. Recent work indicates
that γ-H2AX detection may become a powerful tool for monitoring genotoxic events associated with cancer development and tumor
progression. 相似文献
12.
Regulation of Toll-like receptors in human monocytes and dendritic cells 总被引:45,自引:0,他引:45
Visintin A Mazzoni A Spitzer JH Wyllie DH Dower SK Segal DM 《Journal of immunology (Baltimore, Md. : 1950)》2001,166(1):249-255
A number of pathogens induce immature dendritic cells (iDC) to migrate to lymphoid organs where, as mature DC (mDC), they serve as efficient APC. We hypothesized that pathogen recognition by iDC is mediated by Toll-like receptors (TLRs), and asked which TLRs are expressed during the progression of monocytes to mDC. We first measured mRNA levels for TLRs 1-5 and MD2 (a protein required for TLR4 function) by Northern analysis. For most TLRs, message expression decreased severalfold as monocytes differentiated into iDC, but opposing this trend, TLR3 and MD2 showed marked increases during iDC formation. When iDC were induced to mature with LPS or TNF-alpha, expression of most TLRs transiently increased and then nearly disappeared. Stimulation of iDC, but not mDC, with LPS resulted in the activation of IL-1 receptor-associated kinase, an early component in the TLR signaling pathway, strongly suggesting that LPS signals through a TLR. Surface expression of TLRs 1 and 4, as measured by mAb binding, was very low, corresponding to a few thousand molecules per cell in monocytes, and a few hundred or less in iDC. We conclude that TLRs are expressed in iDC and are involved in responses to at least one pathogen-derived substance, LPS. If TLR4 is solely responsible for LPS signaling in humans, as it is in mice, then its extremely low surface expression implies that it is a very efficient signal transducer in iDC. 相似文献
13.
Ziegelstein RC Xiong Y He C Hu Q 《Biochemical and biophysical research communications》2006,342(1):153-163
Extracellular Ca(2+) concentration ([Ca(2+)](o)) regulates the functions of many cell types through a G protein-coupled [Ca(2+)](o)-sensing receptor (CaR). Whether the receptor is functionally expressed in vascular endothelial cells is largely unknown. In cultured human aortic endothelial cells (HAEC), RT-PCR yielded the expected 555-bp product corresponding to the CaR, and CaR protein was demonstrated by fluorescence immunostaining and Western blot. RT-PCR also demonstrated the expression in HAEC of alternatively spliced variants of the CaR lacking exon 5. Although stimulation of fura 2-loaded HAEC by several CaR agonists (high [Ca(2+)](o), neomycin, and gadolinium) failed to increase intracellular Ca(2+) concentration ([Ca(2+)](i)), the CaR agonist spermine stimulated an increase in [Ca(2+)](i) that was diminished in buffer without Ca(2+) and was abolished after depletion of an intracellular Ca(2+) pool with thapsigargin or after blocking IP(3)- and ryanodine receptor-mediated Ca(2+) release with xestospongin C and with high concentration ryanodine, respectively. Spermine stimulated an increase in DAF-FM fluorescence in HAEC, consistent with NO production. Both the increase in [Ca(2+)](i) and in NO production were reduced or absent in HAEC transfected with siRNA specifically targeted to the CaR. HAEC express a functional CaR that responds to the endogenous polyamine spermine with an increase in [Ca(2+)](i), primarily due to release of IP(3)- and ryanodine-sensitive intracellular Ca(2+) stores, leading to the production of NO. Expression of alternatively spliced variants of the CaR may result in the absence of a functional response to other known CaR agonists in HAEC. 相似文献
14.
Stefan K. Drexler Brian M. Foxwell 《The international journal of biochemistry & cell biology》2010,42(4):506-518
The role of Toll-like receptors (TLRs) in innate immunity and their ability to recognise microbial products has been well characterised. TLRs are also able to recognise endogenous molecules which are released upon cell damage and necrosis and have been shown to be present in numerous autoimmune diseases. Therefore, the release of endogenous TLR ligands during inflammation and consequently the activation of TLR signalling pathways may be one mechanism initiating and driving autoimmune diseases. An increasing body of circumstantial evidence implicates a role of TLR signalling in systemic lupus erythematosus (SLE), atherosclerosis, asthma, type 1 diabetes, multiple sclerosis, bowl inflammation and rheumatoid arthritis (RA). Although at present their involvement is not comprehensively defined. However, future therapies targeting individual TLRs or their signalling transducers may provide a more specific way of treating inflammatory diseases without global suppression of the immune system. 相似文献
15.
Kathryn E. Smith Scott A. Metzler James N. Warnock 《Biomechanics and modeling in mechanobiology》2010,9(1):117-125
Mechanical in vitro preconditioning of tissue engineered heart valves is viewed as an essential process for tissue development
prior to in vivo implantation. However, a number of pro-inflammatory genes are mechanosensitive and their elaboration could
elicit an adverse response in the host. We hypothesized that the application of normal physiological levels of strain to isolated
valve interstitial cells would inhibit the expression of pro-inflammatory genes. Cells were subjected to 0, 5, 10, 15 and
20% strain. Expression of VCAM-1, MCP-1, GM-CSF and OPN was then measured using qRT-PCR. With the exception of OPN, all genes
were significantly up regulated when no strain was applied. MCP-1 expression was significantly lower in the presence of strain,
although strain magnitude did not affect the expression level. VCAM-1 and GM-CSF had the lowest expression levels at 15% strain,
which represent normal physiological conditions. These findings were confirmed using confocal microscopy. Additionally, pSMAD
2/3 and IκBα expression were imaged to elucidate potential mechanisms of gene expression. Data showed that 15% strain increased
pSMAD 2/3 expression and prevented phosphorylation of IκBα. In conclusion, cyclic strain reduces expression of pro-inflammatory
genes, which may be beneficial for the in vitro pre-conditioning of tissue engineered heart valves. 相似文献
16.
Xinmei Wang PhD Mir S. Ali PhD Carla M. R. Lacerda PhD 《Journal of cellular biochemistry》2019,120(7):11158-11171
Both aortic and mitral valves calcify in pathological conditions; however, the prevalence of aortic valve calcification is high whereas mitral valve leaflet calcification is somewhat rare. Patterns of valvular calcification may differ due to valvular architecture, but little is known to that effect. In this study, we investigated the intrinsic osteogenic differentiation potential of aortic versus mitral valve interstitial cells provided minimal differentiation conditions. For the assessment of calcification at the cellular level, we used classic inducers of osteogenesis in stem cells: β-glycerophosphate (β-Gly), dexamethasone (Dex), and ascorbate (Asc). In addition to proteomic analyses, osteogenic markers and calcium precipitates were evaluated across treatments of aortic and mitral valve cells. The combination of β-Gly, Asc, and Dex induced aortic valve interstitial cells to synthesize extracellular matrix, overexpress osteoblastic markers, and deposit calcium. However, no strong evidence showed the calcification of mitral valve interstitial cells. Mitral cells mainly responded to Asc and Dex by cell activation. These findings provide a deeper understanding of the physiological properties of aortic and mitral valves and tendencies for calcific changes within each valve type, contributing to the development of future therapeutics for heart valve diseases. 相似文献
17.
18.
S R Bornstein R R Schumann V Rettori S M McCann K Zacharowski 《Hormones et métabolisme》2004,36(7):470-473
Toll-like receptors (TLRs) are key elements in the innate immune response, functioning as pattern-recognition receptors for the detection and response to endotoxins and other microbial ligands. Inflammatory cytokines play an important role in the activation of the hypothalamic-pituitary-adrenal HPA axis during inflammation and sepsis. The newly recognized major role of TLR2 and TLR4 and the adrenal stress response during critical illnesses such as inflammation and sepsis demand comprehensive analysis of their interactions. Therefore, we analyzed TLR2 and TLR4 expression in human adrenal glands. Western blot analysis demonstrated the expression of TLR2 and TLR4 in the human adrenocortical cell line NCI-H295. Immunohistochemical analysis of normal human adrenal glands revealed TLR2 and TLR4 expression in the adrenal cortex, but not in the adrenal medulla. Considering the crucial role of the HPA axis and the innate immune response during acute sepsis or septic shock, elucidating the functional interaction of these systems should be of great clinical relevance. 相似文献
19.
20.