scholarly journals Lys694Arg polymorphism leads to blunted responses to LPS by interfering TLR4 with recruitment of MyD88

2020 ◽  
pp. 175342592092747
Author(s):  
Yajie Yang ◽  
Yan Hu ◽  
Yile Zhou ◽  
Tao Liang ◽  
Haihong Tang ◽  
...  
Keyword(s):  
Inflammatory Factors ◽  
Myeloid Differentiation ◽  
Study Group ◽  
Tlr4 Expression ◽  
Wild Type ◽  
Human Embryonic Kidney ◽  
Gram Negative ◽  
Tnf Α ◽  
Polymorphic Variants ◽  
Myeloid Differentiation Factor

TLR4 polymorphisms such as Asp299Gly and Thr399Ile related to Gram-negative sepsis have been reported to result in significantly blunted responsiveness to LPS. Our study group previously screened other TLR4 polymorphic variants by checking the NF-κB activation in comparison to wild type (WT) TLR4 in human embryonic kidney 293T cells. In this study, we found that the Lys694Arg (K694R) polymorphism reduced the activation of NF-κB, and the production of downstream inflammatory factors IL-1, TNF-α and IL-6, representing the K694R polymorphism, led to blunted responsiveness to LPS. Then, we examined the influence of the K694R polymorphism on total and cell-surface TLR4 expression by Western blotting and flow cytometry, respectively, but observed no differences between the K694R polymorphism and WT TLR4. We also used co-immunoprecipitation to determine the interaction of the K694R polymorphism and WT TLR4 with their co-receptor myeloid differentiation factor 2 (MD2) and their downstream signal adaptor MyD88. We found that K694R reduced the recruitment of MyD88 in TLR4 signalling but had no impact on the interaction with MD2.

scholarly journals Lipopolysaccharide-Trap-Fc, a Multifunctional Agent To Battle Gram-Negative Bacteria

2009 ◽  
Vol 77 (7) ◽  
pp. 2925-2931 ◽  
Author(s):  
Philipp Groß ◽  
Katharina Brandl ◽  
Christine Dierkes ◽  
Jürgen Schölmerich ◽  
Bernd Salzberger ◽  
...  
Keyword(s):  
Myeloid Differentiation ◽  
Gram Negative Bacteria ◽  
Bacterial Sepsis ◽  
Tlr Signaling ◽  
Monocytic Cells ◽  
Gram Negative ◽  
The Family ◽  
Myeloid Differentiation Factor ◽  
Lps Treatment

ABSTRACT The family of Toll-like receptors (TLRs) plays a pivotal role in host defense against pathogens. However, overstimulation of these receptors may lead to uncontrolled general inflammation and eventually to systemic organ dysfunction or failure. With the intent to control overwhelming inflammation during gram-negative bacterial sepsis, we constructed soluble fusion proteins of the lipopolysaccharide (LPS)-receptor complex to modulate TLR signaling in multiple ways. The extracellular domain of mouse TLR4 and mouse myeloid differentiation factor 2 (MD-2) fusions (LPS-Trap) were linked to human immunoglobulin G Fc domains (LPS-Trap-Fc). In addition to the ability to bind LPS or gram-negative bacteria and to inhibit interleukin-6 secretion of monocytic cells after LPS treatment, LPS-Trap-Fc was able to opsonize fluorescent Escherichia coli particles. This led to enhancement of phagocytosis by monocytic cells which was strictly dependent on the presence of the Fc region. Moreover, only LPS-Trap-Fc- and not LPS-Trap-coated bacteria were sensitized to complement killing. Therefore, LPS-Trap-Fc not only neutralizes LPS but also, after binding to bacteria, enhances phagocytosis and complement-mediated killing and could thus act as a multifunctional agent to fight gram-negative bacteria in vivo.

scholarly journals Aryl Hydrocarbon Receptor Modulates the Expression of TNF-α and IL-8 in Human Sebocytes via the MyD88-p65NF-κB/p38MAPK Signaling Pathways

2018 ◽  
Vol 11 (1) ◽  
pp. 41-51 ◽  
Author(s):  
Xiao-Xiao Hou ◽  
Guangjie Chen ◽  
Amir M. Hossini ◽  
Tingting Hu ◽  
Lanqi Wang ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Physiological Stress ◽  
Acne Vulgaris ◽  
Receptor Protein ◽  
Inflammatory Factors ◽  
Induced Expression ◽  
Aryl Hydrocarbon ◽  
Tnf Α ◽  
P38mapk Signaling ◽  
Myeloid Differentiation Factor

Activation of Toll-like receptor (TLR)-2 and subsequent inflammatory response contribute to lesion development in acne vulgaris. A cross-talk between aryl hydrocarbon receptor (AhR), a cytosolic receptor protein that responds to environmental and physiological stress, and TLRs has recently been reported. In this study, we explored the possible role of AhR in the effects induced on cultured human SZ95 sebocytes by peptidoglycan (PGN), a classic TLR2 agonist. PGN-induced secretion of inflammatory factors TNF-α and IL-8 in human SZ95 sebocytes was suppressed after knockdown of AhR and pretreatment with the AhR antagonist CH223191. In addition, the AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) enhanced TNF-α and IL-8 secretion in PGN-pretreated sebocytes. Furthermore, PGN-induced expression of myeloid differentiation factor 88 (MyD88), phospho-p38MAPK (p-p38MAPK), and p-p65NF-κB was strengthened by TCDD and repressed by CH223191. AhR inhibition by transfecting shRNA blocked the ability of PGN to stimulate phosphorylation of p38MAPK and p65NF-κB in SZ95 sebocytes. Overall, these data demonstrate that AhR is able to modulate PGN-induced expression of TNF-α and IL-8 in human SZ95 sebocytes involving the MyD88-p65NF-κB/p38MAPK signaling pathway, which probably indicates a new mechanism in TLR2-mediated acne.

scholarly journals Follistatin-Like 1 Attenuation Suppresses Intervertebral Disc Degeneration in Mice through Interacting with TNF-α and Smad Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Shaoyi Wang ◽  
Jianlu Wei ◽  
Jie Shi ◽  
Qiting He ◽  
Xiaocong Zhou ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Inflammatory Diseases ◽  
Morphological Changes ◽  
Intervertebral Discs ◽  
Inflammatory Factors ◽  
Wild Type ◽  
Tnf Α

Background. Inflammation plays an important role in intervertebral disc degeneration (IDD). The protein follistatin-like 1 (FSTL1) plays a proinflammatory role in a variety of inflammatory diseases. Objectives. The purpose of this study was to investigate whether IDD could be delayed by inhibiting FSTL-1 expression. Methods. We established a puncture-induced IDD model in wild-type and FSTL-1+/- mice and collected intervertebral discs (IVDs) from the mice. Safranin O staining was used to detect cartilage loss of IVD tissue, and HE staining was used to detect morphological changes of IVD tissue. We measured the expression of FSTL-1 and related inflammatory indicators in IVD tissues by immunohistochemical staining, real-time PCR, and Western blotting. Results. In the age-induced model of IDD, the level of FSTL-1 increased with the exacerbation of degeneration. In the puncture-induced IDD model, FSTL-1-knockdown mice showed a reduced degree of degeneration compared with that of wild-type mice. Further experiments showed that FSTL-1 knockdown also significantly reduced the level of related inflammatory factors in IVD. In vitro experiments showed that FSTL-1 knockdown significantly reduced TNF-α-induced inflammation. Specifically, the expression levels of the inflammatory factors COX-2, iNOS, MMP-13, and ADAMTS-5 were reduced. Knockdown of FSTL-1 attenuated inflammation by inhibiting the expression of P-Smad1/5/8, P-Erk1/2, and P-P65. Conclusion. Knockdown of FSTL-1 attenuated inflammation by inhibiting the TNF-α response and Smad pathway activity and ultimately delayed IDD.

scholarly journals The role of Toll-like receptor 4 in apoptosis of brain tissue after induction of intracerebral hemorrhage

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Xiaowei Fei ◽  
Yeting He ◽  
Jia Chen ◽  
Weitao Man ◽  
Chen Chen ◽  
...  
Keyword(s):  
Intracerebral Hemorrhage ◽  
Knockout Mice ◽  
Neuronal Apoptosis ◽  
Inflammatory Factors ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Toll Like Receptor 4 ◽  
Tnf Α ◽  
Apoptotic Effect

Abstract Background Inflammation and apoptosis caused by intracerebral hemorrhage (ICH) are two important factors that affect patient prognosis and survival. Toll-like receptor 4 (TLR4) triggers activation of the inflammatory pathway, causing synthesis and release of inflammatory factors. The inflammatory environment also causes neuronal apoptosis. However, no studies have reported the role of TLR4 in inflammation and apoptosis. Methods We performed survival curve analysis and behavioral scores on TLR4 knockout mice and wild-type mice after inducing ICH. We used TLR4 knockout mice and wild-type mice to make ICH models with type VII collagenase and explored the link between TLR4 in inflammation and apoptosis. We used Western blot to detect the expression of apoptosis-related proteins, inflammatory factors, and their receptors at different time points after ICH induction. The effects of TLR4 on apoptosis were observed by TUNEL, Hoechst, and HE staining techniques. The association with TLR4 in inflammation and apoptosis was explored using IL-1β and TNF-α antagonists. Data conforming to a normal distribution are expressed as mean ± standard deviation. Grade and quantitative data were compared with rank sum test and t test between two groups. P < 0.05 was considered statistically significant. Results TLR4 knockout significantly increased the survival rate of ICH mice. The scores of TLR4 knockout mice were significantly lower than those of wild-type mice. We found that TLR4 knockout mice significantly inhibited apoptosis and the expression of inflammatory factors after the induction of ICH. The apoptosis of ICH-induced mice was significantly improved after injecting IL-1β and TNF-α antagonists. Moreover, the anti-apoptotic effect of the antagonist in wild-type mice is more pronounced. A single injection of the antagonist failed to improve apoptosis in TLR4 knockout mice. Conclusions We conclude that TLR4-induced inflammation after ICH promotes neuronal apoptosis. IL-1β and TNF-α antagonists attenuate this apoptotic effect. Therefore, targeting TLR4 in patients with clinical ICH may attenuate inflammatory response, thereby attenuating apoptosis and improving prognosis.

scholarly journals MyD88, but Not Toll-Like Receptors 4 and 2, Is Required for Efficient Clearance of Brucella abortus

2005 ◽  
Vol 73 (8) ◽  
pp. 5137-5143 ◽  
Author(s):  
David S. Weiss ◽  
Kiyoshi Takeda ◽  
Shizuo Akira ◽  
Arturo Zychlinsky ◽  
Edgardo Moreno
Keyword(s):  
Myeloid Differentiation ◽  
Toll Like Receptor ◽  
Immunostimulatory Activity ◽  
Toll Like Receptor 4 ◽  
Gram Negative ◽  
Macrophage Response ◽  
Tlr4 Activation ◽  
Myeloid Differentiation Factor ◽  
Kinetics Of

ABSTRACT It is not clear how the host initially recognizes and responds to infection by gram-negative pathogenic Brucella spp. It was previously shown (D. S. Weiss, B. Raupach, K. Takeda, S. Akira, and A. Zychlinsky, J. Immunol. 172:4463-4469, 2004) that the early macrophage response against gram-negative bacteria is mediated by Toll-like receptor 4 (TLR4), which signals in response to lipopolysaccharide (LPS). Brucella, however, has a noncanonical LPS which does not have potent immunostimulatory activity. We evaluated the kinetics of TLR4 activation and the cytokine response in murine macrophages after Brucella infection. We found that during infection of macrophages, Brucella avoids activation of TLR4 at 6 h but activates TLR4, TLR2, and myeloid differentiation factor 88 (MyD88) at 24 h postinfection. Interestingly, even though its activation is delayed, MyD88 is important for host defense against Brucella infection in vivo, since MyD88−/− mice do not clear the bacteria as efficiently as wild-type, TLR4−/−, TLR2−/−, or TLR4/TLR2−/− mice.

scholarly journals The clinical evaluation of combined detection of microcirculation, lipid metabolism, and inflammatory-related factors in the treatment of diabetic nephropathy with atorvastatin

2019 ◽  
Vol 17 ◽  
pp. 205873921984783 ◽  
Author(s):  
Haicheng Wang ◽  
Zhengfang Zhang ◽  
Jiali Sun
Keyword(s):  
Diabetic Nephropathy ◽  
Statistical Significance ◽  
Density Lipoprotein ◽  
Post Treatment ◽  
Inflammatory Factors ◽  
Control Group ◽  
Study Group ◽  
Related Factors ◽  
Tnf Α ◽  
Pre Treatment

This study was designed to analyze the effects of atorvastatin on microcirculation, blood lipids, inflammatory factors, and characteristic markers in patients with diabetic nephropathy. A total of 170 patients with diabetic nephropathy randomly divided into control and study groups with 85 patients in each group. The control group was treated with diet and lifestyle intervention, and hypoglycemic drugs. The study group was additionally treated with atorvastatin. Nitric oxide (NO), endothelin-1 (ET-1), thromboxane-2 (TXB2), 6-ketone-prostaglandin F-1α (6-Keto-PGF-1α), superoxide dismutase (SOD), total cholesterol (TC), triacylglycerols (TGs), low-density lipoprotein (LDL), high-density lipoprotein (HDL), C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), homocysteine (Hcy), cystatin C (CysC), and vascular endothelial growth factor (VEGF) levels were observed for 8 weeks. Post-treatment of atorvastatin, the levels of NO, 6-Keto-PGF-1α, and SOD were significantly higher than pre-treatment in both groups, while the levels of ET-1 and TXB2 were lower than pre-treatment ( P < 0.05). The levels of NO, 6-Keto-PGF-1α, and SOD in the study group post-treatment were significantly higher ( P < 0.05) than the control group, and the levels of ET-1 and TXB2 in the study group were lower than the control group. After 8 weeks, the levels of TC, TG, and LDL were significantly lower, while the level of HDL was significantly higher in the study group. The level of TC was lower in the control group of post-treatment, while the HDL level was higher than pre-treatment ( P < 0.05). The levels of CRP, TNF-α, and IL-6 in the study group of post-treatment were significantly lower than pre-treatment comparing to the control group ( P < 0.05). There was no statistical significance ( P > 0.05) for above-mentioned indicators in control groups of pre- and post-treatment. The levels of VEGF, CysC, and Hcy in the two groups were lower than pre-treatment. Atorvastatin could effectively improve all the study parameters.

scholarly journals MYCOBACTERIUM TUBERCULOSIS SISTEM IMUN ALAMIAH TERKAIT PENERIMANYA

2016 ◽  
Vol 19 (1) ◽  
pp. 45
Author(s):  
Jusak Nugraha
Keyword(s):  
Immune Response ◽  
Inflammatory Cytokine ◽  
Adaptive Immune Response ◽  
Innate Immune ◽  
Myeloid Differentiation ◽  
Toll Like Receptor ◽  
Protective Function ◽  
Adaptive Immune ◽  
Tnf Α ◽  
Myeloid Differentiation Factor

Various attemp to investigate immune response towards tuberculosis has been done in order to eradicate or to make vaccination against tuberculosis (TB) effectively. Recently it is known that innate immunity has an important role in immunity to TB despite adaptive immune response, because it was proved that adaptive immune response alone was not sufficient to eradicate this microorganism thoroughly and completely in patient’s body. After Toll-Like Receptor (TLR) was found in the end of the 20th century, many progresses has been obtained in understanding about the activation of this innate immune response. But it is still needed to understand more deeply in the immune response to M. tuberculosis to lead the development of therapy or vaccination that bring into more precise target. The activation through TLR by parts of Mycobacterium induce cytoplasm protein adaptor MyD88 (Myeloid Differentiation factor 88). MyD88 has the function to activate NF- κB and secrete pro-inflammatory cytokine such as TNF-α, IL-6, IL-12. Involvement of MyD88 is not solely dependent of TLR2 receptor and there are another pathways to induce protective function of immunocompetent cells in TB.

scholarly journals Changes in intestinal flora, TNF-α, L-17, and IL-6 levels in patients with gestational diabetes mellitus

2018 ◽  
Vol 16 ◽  
pp. 205873921879355 ◽  
Author(s):  
Haiyan Yu ◽  
Zhonglan Liu ◽  
Shaohua Dong
Keyword(s):  
Diabetes Mellitus ◽  
Risk Factors ◽  
Logistic Regression ◽  
Gestational Diabetes ◽  
Intestinal Flora ◽  
Inflammatory Factors ◽  
Control Group ◽  
Study Group ◽  
Multivariate Logistic Regression ◽  
Tnf Α

To study the changes in intestinal flora and different inflammatory factors in patients with gestational diabetes mellitus (GDM), a total of 80 patients with GDM treated in our hospital were selected as the study group. Meanwhile, another 60 normal pregnant women were selected as the control group. The contents of intestinal Bifidobacterium, Lactobacillus, and Bacteroides were measured in both groups followed by comparison of the incidence of intestinal flora imbalance. In the meantime, the levels of tumor necrosis factor alpha (TNF-α), interleukin-17 (IL-17), and interleukin-6 (IL-6) in serum were detected and compared between those two groups. Afterwards, multivariate logistic regression was used to analyze the risk factors related to GDM. The number of Bifidobacterium, Lactobacillus, and Bacteroides in the study group was significantly less than those in the control group. The incidence of intestinal flora imbalance in the study group was 33.75%, which is higher than that in the control group. The serum levels of inflammatory factors, including TNF-α, IL-17, and IL-6 in the study group were significantly higher than those in the control group. The result of multivariate logistic regression analysis showed that Bifidobacterium, Lactobacilli, Bacteroides, TNF-α, IL-17, and IL-6 were risk factors related to GDM. Patients with GDM are prone to intestinal flora imbalance with elevated different inflammatory, which affects immune function in patients and may play an important role in the development of diabetes mellitus.

scholarly journals Expression of human TLR4/myeloid differentiation factor 2 directs an early innate immune response associated with modest increases in bacterial burden during Coxiella burnetii infection

2019 ◽  
Vol 25 (7) ◽  
pp. 401-411
Author(s):  
Amanda Robison ◽  
Deann T Snyder ◽  
Kelly Christensen ◽  
Emily Kimmel ◽  
Adeline M Hajjar ◽  
...  
Keyword(s):  
Coxiella Burnetii ◽  
Hematopoietic Cells ◽  
Adaptor Protein ◽  
Myeloid Differentiation ◽  
Target Cells ◽  
Lung Pathology ◽  
Bacterial Burden ◽  
Wild Type ◽  
Differentiation Factor ◽  
Myeloid Differentiation Factor

Human TLR4 (hTLR4) and mouse TLR4 molecules respond differently to hypo-acylated LPS. The LPS of Coxiella burnetii is hypo-acylated and heavily glycosylated and causes a minimal response by human cells. Thus, we hypothesized that mice expressing hTLR4 molecules would be more susceptible to C. burnetii infection. Our results show that transgenic mice expressing hTLR4 and the human myeloid differentiation factor 2 (MD-2) adaptor protein (hTLR4/MD-2) respond similarly to wild type mice with respect to overall disease course. However, differences in bacterial burdens in tissues were noted, and lung pathology was increased in hTLR4/MD2 compared to wild type mice. Surprisingly, bone marrow chimera experiments indicated that hTLR4/MD-2 expression on non-hematopoietic cells, rather than the target cells for C. burnetii infection, accounted for increased bacterial burden. Early during infection, cytokines involved in myeloid cell recruitment were detected in the plasma of hTLR4/MD2 mice but not wild type mice. This restricted cytokine response was accompanied by neutrophil recruitment to the lung in hTLR4/MD2 mice. These data suggest that hTLR4/MD-2 alters early responses during C. burnetii infection. These early responses are precursors to later increased bacterial burdens and exacerbated pathology in the lung. Our data suggest an unexpected role for hTLR4/MD-2 in non-hematopoietic cells during C. burnetii infection.

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