scholarly journals Toll-like receptor 2 downregulation and cytokine dysregulation predict mortality in patients with Staphylococcus aureus bacteremia

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Nak-Hyun Kim ◽  
Ji Yeon Sung ◽  
Yoon Jung Choi ◽  
Su-Jin Choi ◽  
Soyeon Ahn ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Tertiary Care ◽  
High Sensitivity ◽  
Mrna Levels ◽  
Toll Like Receptor ◽  
Tlr2 Expression ◽  
Staphylococcus Aureus Bacteremia ◽  
Tnf Α ◽  
Toll Like Receptor 2 ◽  
Cytokine Dysregulation

Abstract Background Staphylococcus aureus bacteremia (SAB) presents heterogeneously, owing to the differences in underlying host conditions and immune responses. Although Toll-like receptor 2 (TLR2) is important in recognizing S. aureus, its function during S. aureus infection remains controversial. We aimed to examine the association of TLR2 expression and associated cytokine responses with clinical SAB outcomes. Methods Patients from a prospective SAB cohort at two tertiary-care medical centers were enrolled. Blood was sampled at several timepoints (≤5 d, 6–9 d, 10–13 d, 14–19 d, and ≥ 20 d) after SAB onset. TLR2 mRNA levels were determined via real-time PCR and serum tumor necrosis factor [TNF]-α, interleukin [IL]-6, and IL-10 levels were analyzed with multiplex-high-sensitivity electrochemiluminescent ELISA. Results TLR2 levels varied among 59 SAB patients. On days 2–5, TLR2 levels were significantly higher in SAB survivors than in healthy controls (p = 0.040) and slightly but not significantly higher than non-survivors (p = 0.120), and SAB patients dying within 7 d had lower TLR2 levels than survivors (P = 0.077) although statistically insignificant. IL-6 and IL-10 levels were significantly higher in non-survivors than in survivors on days 2–5 post-bacteremia (P = 0.010 and P = 0.021, respectively), and those dying within 7 d of SAB (n = 3) displayed significantly higher IL-10/TNF-α ratios than the survivors did (P = 0.007). Conclusion TLR2 downregulation and IL-6 and IL-10 concentrations suggestive of immune dysregulation during early bacteremia may be associated with mortality from SAB. TLR2 expression levels and associated cytokine reactions during early-phase SAB may be potential prognostic factors in SAB, although larger studies are warranted.

scholarly journals A Novel Mechanism of Carvedilol Efficacy for Rosacea Treatment: Toll-Like Receptor 2 Inhibition in Macrophages

2021 ◽  
Vol 12 ◽  
Author(s):  
Jiawen Zhang ◽  
Peiyu Jiang ◽  
Lei Sheng ◽  
Yunyi Liu ◽  
Yixuan Liu ◽  
...  
Keyword(s):  
Raw 264.7 Cells ◽  
Pathological Examination ◽  
Raw 264.7 ◽  
Toll Like Receptor ◽  
Tlr2 Expression ◽  
Inflammatory Status ◽  
Tnf Α ◽  
Toll Like Receptor 2 ◽  
Skin Samples

BackgroundRosacea, a chronic inflammatory skin disorder etiologically associated with immune cells and the antibacterial peptide cathelicidin LL-37, can be effectively treated by oral carvedilol administration.ObjectiveTo investigate the molecular mechanisms underlying carvedilol efficacy in rosacea treatment.MethodsSkin samples of patients with rosacea were subjected to histopathological (hematoxylin and eosin) and immunohistochemical (CD68, Toll-like receptor 2 (TLR2), kallikrein 5, cathelicidin, TNF-α, and IL-1β) evaluation. An in vivo murine rosacea-like inflammation model was established by LL-37 intradermal injection with or without carvedilol gavage-based pretreatment. Erythema proportion (Image J) and skin redness (L*a*b colorimetry) were quantified. Murine skin samples underwent pathological examination for inflammatory status and immunofluorescence staining. Murine skin and lipopolysaccharide-stimulated RAW 264.7 cells with or without carvedilol pretreatment were evaluated by quantitative reverse transcription-polymerase chain reaction and western blotting. Clinical facial images of patients were obtained using the VISIA skin analysis system before, 4, and 6 months following oral carvedilol administration.ResultsRosacea skin lesions exhibited more pronounced inflammatory cell infiltration than peripheral areas, with profound macrophage infiltration and inflammatory cytokines (TLR2, kallikrein 5, cathelicidin, TNF-α, and IL-1β). In vivo, carvedilol alleviated inflammation in LL-37 mice, down-regulating TLR2, KLK5, and cathelicidin expression. In vitro, carvedilol decreased TLR2 expression in RAW 264.7 cells, further reducing KLK5 secretion and LL-37 expression and ultimately inhibiting rosacea-like inflammatory reactions. Clinical manifestations and facial redness obviously improved during 6-month follow-up with systemic carvedilol administration.ConclusionCarvedilol is effective against rosacea, with inhibition of macrophage TLR2 expression as a novel anti-inflammatory mechanism.

scholarly journals Toll-Like Receptor 2 Mediates Alveolar Macrophage Response to Pneumocystis murina

2006 ◽  
Vol 74 (3) ◽  
pp. 1857-1864 ◽  
Author(s):  
Chen Zhang ◽  
Shao-Hung Wang ◽  
Mark E. Lasbury ◽  
Dennis Tschang ◽  
Chung-Ping Liao ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Alveolar Macrophages ◽  
Nuclear Translocation ◽  
Innate Immune ◽  
Hek293 Cells ◽  
Mrna Levels ◽  
Toll Like Receptor ◽  
Tnf Α ◽  
Toll Like Receptor 2

ABSTRACT The innate immune response to Pneumocystis infection is not well understood. In this study, normal C57BL/6 mouse alveolar macrophages were found to respond to Pneumocystis murina organisms through Toll-like receptor 2 (TLR2), leading to the nuclear translocation of NF-κB and the production of proinflammatory cytokine tumor necrosis factor alpha (TNF-α) and chemokine macrophage inflammatory protein 2 (MIP-2). P. murina stimulation of normal alveolar macrophages from C57BL/6 mice resulted in increased TLR2 transcription but not increased TLR4 transcription. In gain-of-function studies with HEK293 cells expressing TLR2 or TLR4, only TLR2 was found to stimulate an NF-κB response to P. murina. TNF-α and MIP-2 production in response to P. murina by mouse alveolar macrophages was inhibited by a monoclonal antibody that specifically blocked the ligand-binding ability of TLR2. Alveolar macrophages from TLR2 knockout (TLR2−/−) mice showed little increase in TNF-α and MIP-2 mRNA levels upon P. murina stimulation. An in vivo study showed that TLR2−/− mice challenged with P. murina had reduced cytokine responses. These results indicate that TLR2 plays a major role in the innate immune response to P. murina.

scholarly journals The Staphylococcus aureus Lipoprotein SitC Colocalizes with Toll-Like Receptor 2 (TLR2) in Murine Keratinocytes and Elicits Intracellular TLR2 Accumulation

2010 ◽  
Vol 78 (10) ◽  
pp. 4243-4250 ◽  
Author(s):  
P. Müller ◽  
M. Müller-Anstett ◽  
J. Wagener ◽  
Q. Gao ◽  
S. Kaesler ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Host Cells ◽  
Hek293 Cells ◽  
Toll Like Receptor ◽  
Intracellular Accumulation ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Tlr2 Activation ◽  
Toll Like Receptor 2 ◽  
Factor Alpha

ABSTRACT SitC is one of the predominant lipoproteins in Staphylococcus aureus. Recently, SitC was shown to be capable of stimulating Toll-like receptor 2 (TLR2), but the mechanism of TLR2 activation by SitC has not been analyzed in detail so far. In this study, we purified C-terminally His-tagged SitC (SitC-His) from Staphylococcus aureus. SitC-His induced interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) release in human monocytes and also NF-κB activation in TLR2-transfected HEK293 cells, indicating TLR2-specific activation. SitC not only induced a TLR2-dependent release of IL-6 in primary murine keratinocytes (MKs) but also induced intracellular accumulation of TLR2, which was time and concentration dependent. Cy2-labeled SitC-His colocalized specifically with TLR2 in MKs and was also internalized in TLR2 knockout MKs, suggesting a TLR2-independent uptake. Neither activation nor colocalization of SitC-His was observed with TLR4 or Nod2. The results show that the native lipoprotein SitC-His specifically colocalizes with TLR2, is internalized by host cells, induces proinflammatory cytokines, and triggers intracellular accumulation of TLR2.

scholarly journals Human Mast Cell Activation by Staphylococcus aureus: Interleukin-8 and Tumor Necrosis Factor Alpha Release and the Role of Toll-Like Receptor 2 and CD48 Molecules

2008 ◽  
Vol 76 (10) ◽  
pp. 4489-4497 ◽  
Author(s):  
Claudio M. Rocha-de-Souza ◽  
Beata Berent-Maoz ◽  
David Mankuta ◽  
Allon E. Moses ◽  
Francesca Levi-Schaffer
Keyword(s):  
Staphylococcus Aureus ◽  
Mast Cells ◽  
Tumor Necrosis ◽  
Toll Like Receptor ◽  
Atopic Diseases ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Toll Like Receptor 2 ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT The ability of Staphylococcus aureus to invade and survive within host cells is believed to contribute to its propensity to cause persistent and metastatic infections. In addition, S. aureus infections often are associated with atopic diseases such as dermatitis, rhinitis, and asthma. Mast cells, the key cells of allergic diseases, have a pivotal role in innate immunity and have the capacity of phagocytosis, and they can destroy some pathogenic bacteria. However, little is known about the ability of some other bacteria to survive and overcome mast cell phagocytosis. Therefore, we were interested in evaluating the interplay between mast cells and S. aureus. In this study, we show that human cord blood-derived mast cells (CBMC) can be infected by pathogenic S. aureus. S. aureus displayed a high adherence to mast cells as well as invasive and survival abilities within them. However, when infections were performed in the presence of cytochalasin D or when CBMC were preincubated with anti-Toll-like receptor 2 (TLR2) or anti-CD48 antibodies, the invasiveness and the inflammatory response were abrogated, respectively. Furthermore, we observed an increase of TLR2 and CD48 molecules on CBMC after S. aureus infection. The infection of CBMC with S. aureus also caused the release of tumor necrosis factor alpha (TNF-α) and interleukin-8 (IL-8). Both live and killed S. aureus organisms were found to trigger TNF-α and IL-8 release by CBMC in a time-dependent manner. Cumulatively, these findings suggest that S. aureus internalizes and survives in mast cells. This may play an important role in infections and in atopic diseases associated with S. aureus.

scholarly journals Is Cefazolin Inferior to Nafcillin for Treatment of Methicillin-Susceptible Staphylococcus aureus Bacteremia?

2011 ◽  
Vol 55 (11) ◽  
pp. 5122-5126 ◽  
Author(s):  
Shinwon Lee ◽  
Pyoeng Gyun Choe ◽  
Kyoung-Ho Song ◽  
Sang-Won Park ◽  
Hong Bin Kim ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Treatment Failure ◽  
Propensity Scores ◽  
Tertiary Care ◽  
Care Hospital ◽  
Clinical Failure ◽  
Content Type ◽  
Staphylococcus Aureus Bacteremia ◽  
Matched Case ◽  
Control Study

ABSTRACTAbout 20% of methicillin-susceptibleStaphylococcus aureus(MSSA) isolates have a substantial inoculum effect with cefazolin, suggesting that cefazolin treatment may be associated with clinical failure for serious MSSA infections. There are no well-matched controlled studies comparing cefazolin with nafcillin for the treatment of MSSA bacteremia. A retrospective propensity-score-matched case-control study was performed from 2004 to 2009 in a tertiary care hospital where nafcillin was unavailable from August 2004 to August 2006. The cefazolin group (n= 49) included MSSA-bacteremic patients treated with cefazolin during the period of nafcillin unavailability, while the nafcillin group (n= 84) comprised those treated with nafcillin. Treatment failure was defined as a composite outcome of a change of antibiotics due to clinical failure, relapse, and mortality. Of 133 patients, 41 patients from each group were matched by propensity scores. There were no significant differences in baseline characteristics between the matched groups. The treatment failure rates were not significantly different at 4 or 12 weeks (10% [4/41] versus 10% [4/41] at 4 weeks [P> 0.99] and 15% [6/41] versus 15% [6/41] at 12 weeks [P> 0.99]). Cefazolin treatment was interrupted less frequently than nafcillin treatment due to drug adverse events (0% versus 17%;P= 0.02). Cefazolin had clinical efficacy similar to that of nafcillin and was more tolerable than nafcillin for the treatment of MSSA bacteremia.

Oxymatrine inhibits lipopolysaccharide-induced inflammation by down-regulating Toll-like receptor 4/nuclear factor-kappa B in macrophages

2015 ◽  
Vol 93 (4) ◽  
pp. 253-260 ◽  
Author(s):  
Yu Zhang ◽  
Ruhong Yan ◽  
Yae Hu
Keyword(s):  
Nitric Oxide ◽  
Interleukin 1 ◽  
Chinese Herb ◽  
Mrna Levels ◽  
Nuclear Factor ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Anti Inflammatory

Oxymatrine (OMT) is the quinolizidine alkaloid extracted from the Chinese herb Sophora flavescens Ait. that has many pharmacological effects and is used for the treatment of some inflammatory diseases. In this study, RAW264.7 cells and THP-1 differentiated macrophages were pretreated with various concentrations of OMT at 2 h prior to treatment with lipopolysaccharide (LPS) (1.0 μg/mL) for different durations. We detected the anti-inflammatory effect of OMT in LPS-stimulated macrophages and investigated the molecular mechanism. We showed that OMT pretreatment significantly inhibited the LPS-induced secretion of nitric oxide (NO), interleukin-1 beta (IL-1β), and tumor necrosis factor-alpha (TNF-α) in supernatant, attenuated the mRNA levels of inducible nitric oxide synthase (iNOS), IL-1β, TNF-α, and Toll-like receptor 4 (TLR4), increased TLR4 and phosphorylation of inhibitor of kappa B-alpha (p-IBα) in cytosol, and decreased the nuclear level of nuclear factor-κB (NF-κB) p65 in macrophages. In conclusion, OMT exerts anti-inflammatory properties in LPS-stimulated macrophages by down-regulating the TLR4/NF-κB pathway.

scholarly journals A Comparison of Cefazolin Versus Ceftriaxone for the Treatment of Methicillin-Susceptible Staphylococcus aureus Bacteremia in a Tertiary Care VA Medical Center

2018 ◽  
Vol 5 (5) ◽  
Author(s):  
Dustin R Carr ◽  
Usha Stiefel ◽  
Robert A Bonomo ◽  
Christopher J Burant ◽  
Sharanie V Sims
Keyword(s):  
Staphylococcus Aureus ◽  
Treatment Failure ◽  
Medical Center ◽  
Tertiary Care ◽  
Skilled Nursing Facility ◽  
Suppressive Therapy ◽  
Published Data ◽  
Outpatient Parenteral Antimicrobial Therapy ◽  
Staphylococcus Aureus Bacteremia ◽  
Population Potential

Abstract Background Cefazolin and ceftriaxone are frequently used to treat methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia, especially in the realm of outpatient parenteral antimicrobial therapy. Both antimicrobials have been associated with favorable clinical outcomes for mixed MSSA infections. However, limited published data exist specifically comparing the use of these agents for the treatment of MSSA bacteremia. Methods We conducted a retrospective cohort study of Veteran patients with MSSA bacteremia who received ≥14 days of cefazolin or ceftriaxone between 2009 and 2014. Rates of treatment failure were compared between both groups. Treatment failure was defined as therapy extension, incomplete therapy, unplanned oral suppressive therapy, relapse of infection, or hospital admission or surgery within 90 days. Results Out of 71 patients, 38 received treatment with cefazolin and 33 with ceftriaxone. The overall rate of treatment failure was 40.8%, with significantly more failures among patients receiving ceftriaxone (54.5% versus 28.9%; P = .029). Factors associated with treatment failure included longer duration of parenteral therapy, heart failure, and treatment in an external skilled nursing facility as compared with treatment in the Department of Veterans Affairs attached Community Living Center. Conclusions Ceftriaxone had a higher rate of treatment failure than cefazolin for the treatment of MSSA bacteremia in a Veteran population. Potential reasons for this could include the higher protein binding of ceftriaxone, ultimately resulting in lower serum concentrations of free drug, or other unknown factors. Further studies are warranted to confirm these results.

scholarly journals β-arrestin-2 up-regulates toll-like receptor 2 signaling and inhibits apoptosis in human endometrial cancer heterotransplants in nude mice

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Fanling Hong ◽  
Yujun Zhang ◽  
Wenjin Cheng ◽  
Xiuli Sun ◽  
Jianliu Wang
Keyword(s):  
Inflammatory Cytokines ◽  
Nude Mice ◽  
Caspase 3 ◽  
Glycogen Synthase ◽  
Inflammatory Factors ◽  
Toll Like Receptor ◽  
Caspase 9 ◽  
Serine Threonine Kinase ◽  
Tnf Α ◽  
Toll Like Receptor 2

Abstract Background β-arrestin-2(Arr2) functions as an anti-apoptotic factor and affects cell proliferation, but its downstream molecular pathway in endometrial carcinoma (EC) is still unclear. This study aimed to investigate the effects of the stable overexpression of Arr2 on the proliferation and apoptosis of human EC heterotransplants and the expression of associated molecules, including Toll-like receptor 2(TLR2), serine-threonine kinase Akt (Akt), glycogen synthase kinase-3β(GSK3β) and some typical inflammatory cytokines such as NF-κB p56, TNF-α and IL-6 & IL-8. Methods Human EC cell line Ishikawa, stably transfected with Arr2 full-length plasmid, was injected subcutaneously into nude mice. They were treated with 0, 10, 20 mg/kg paclitaxel and the volume and weight of the tumor tissue were measured and calculated. The necrotic index were assessed by H&E staining and microscopic observation. The levels of caspase-3, caspase-9, TLR2, NF-κB p56, Akt, GSK3β were measured by western blot, and the levels of TNF-α, IL-6, IL-8 were measured by real-time PCR. Results We found that Arr2 overexpression promoted the growth of human EC heterotransplants. Arr2 attenuated the promotion of caspase-3 and caspase-9 by paclitaxel and mediated the increase of TLR2 and several inflammatory cytokines. The levels of Akt and GSK3β were not affected. Conclusion Arr2 overexpression was associated with the increase of TLR2 and several inflammatory factors, meanwhile inhibited paclitaxel-induced anti-tumor effect on human EC heterotransplants.

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