Inducible cardiac ischaemia is related to a decrease in the whole-blood Toll-like receptor 2 and 4 response

2012 ◽  
Vol 122 (11) ◽  
pp. 527-533 ◽  
Author(s):  
Ellen H. A. M. Elsenberg ◽  
Dik Versteeg ◽  
Jan-Willem Sels ◽  
Pieter-Jan J. Vlaar ◽  
Monique G. G. Hobbelink ◽  
...  
Keyword(s):  
Whole Blood ◽  
Receptor Activation ◽  
Emission Computed Tomography ◽  
Toll Like Receptor ◽  
Fractional Flow ◽  
Cd11b Expression ◽  
Spect Mpi ◽  
Reversible Defect ◽  
Myocardial Stress ◽  
Inducible Ischaemia

TLR (Toll-like receptor) activation-induced inflammatory responses are important in the progression of atherosclerosis. We previously showed that TLR-dependent leucocyte responsiveness is acutely attenuated following percutaneous coronary intervention or vascular surgery. Furthermore, cytokine release following whole-blood TLR-2 and TLR-4 stimulation is negatively correlated with fractional flow reserve, suggesting that chronic ischaemia can elicit an enhanced inflammatory response. In the present study, we assessed the association between leucocyte TLR-2 and TLR-4 responsiveness and pre-existent and inducible ischaemia in patients undergoing SPECT (single-photon emission computed tomography)-MPI (myocardial perfusion imaging). TLR-2, TLR-4 and CD11b expression on monocytes were measured in blood samples that were obtained from 100 patients with suspected coronary artery disease before and after myocardial stress testing for SPECT-MPI. IL-8 (interleukin-8) levels were determined after whole-blood stimulation with Pam3Cys (TLR-2) and LPS (lipopolysaccharide; TLR-4). On the basis of SPECT-MPI, patients were categorized into three groups: reversible defect, irreversible defect and no defect. Myocardial stress induced a reduction in TLR-4 expression (2.46±0.21 compared with 2.17±0.16 arbitrary units, P=0.001) and CD11b expression (83.2±1.73 compared with 76.0±1.89 arbitrary units, P<0.001). TLR-induced IL-8 production before myocardial stress induction was not associated with the results of SPECT-MPI. However, a significant decrease in IL-8 production following TLR stimulation was observed after stress, which was more pronounced in patients with a reversible defect. In conclusion, inducible ischaemia is associated with a decrease in whole-blood TLR-2 and TLR-4 response. These results point to a regulating role of TLRs in order to prevent excessive inflammatory events known to occur during acute ischaemia.

scholarly journals Differential Effects of Toll-Like Receptor Activation and Differential Mediation by MAP Kinases of Immune Responses in Microglial Cells

2021 ◽  
Author(s):  
Jaedeok Kwon ◽  
Christos Arsenis ◽  
Maria Suessmilch ◽  
Alison McColl ◽  
Jonathan Cavanagh ◽  
...  
Keyword(s):  
Map Kinase ◽  
Microglial Activation ◽  
Map Kinases ◽  
Mrna Level ◽  
Cell Types ◽  
Receptor Activation ◽  
Microglial Cells ◽  
Toll Like Receptor ◽  
Disease States ◽  
Nitrite Production

AbstractMicroglial activation is believed to play a role in many psychiatric and neurodegenerative diseases. Based largely on evidence from other cell types, it is widely thought that MAP kinase (ERK, JNK and p38) signalling pathways contribute strongly to microglial activation following immune stimuli acting on toll-like receptor (TLR) 3 or TLR4. We report here that exposure of SimA9 mouse microglial cell line to immune mimetics stimulating TLR4 (lipopolysaccharide—LPS) or TLR7/8 (resiquimod/R848), results in marked MAP kinase activation, followed by induction of nitric oxide synthase, and various cytokines/chemokines. However, in contrast to TLR4 or TLR7/8 stimulation, very few effects of TLR3 stimulation by poly-inosine/cytidine (polyI:C) were detected. Induction of chemokines/cytokines at the mRNA level by LPS and resiquimod were, in general, only marginally affected by MAP kinase inhibition, and expression of TNF, Ccl2 and Ccl5 mRNAs, along with nitrite production, were enhanced by p38 inhibition in a stimulus-specific manner. Selective JNK inhibition enhanced Ccl2 and Ccl5 release. Many distinct responses to stimulation of TLR4 and TLR7 were observed, with JNK mediating TNF protein induction by the latter but not the former, and suppressing Ccl5 release by the former but not the latter. These data reveal complex modulation by MAP kinases of microglial responses to immune challenge, including a dampening of some responses. They demonstrate that abnormal levels of JNK or p38 signalling in microglial cells will perturb their profile of cytokine and chemokine release, potentially contributing to abnormal inflammatory patterns in CNS disease states.

scholarly journals Toll-like Receptor Activation of Human Cells by Synthetic Triacylated Lipid A-like Molecules

2012 ◽  
Vol 287 (20) ◽  
pp. 16121-16131 ◽  
Author(s):  
Irène Dunn-Siegrist ◽  
Pierre Tissières ◽  
Geneviève Drifte ◽  
Jacques Bauer ◽  
Stéphane Moutel ◽  
...  
Keyword(s):  
Lipid A ◽  
Receptor Activation ◽  
Human Cells ◽  
Toll Like Receptor

The dysfunctional innate immune response triggered by Toll-like receptor activation is restored by TLR7/TLR8 and TLR9 ligands in cutaneous lichen planus

2014 ◽  
Vol 172 (1) ◽  
pp. 48-55 ◽  
Author(s):  
R. Domingues ◽  
G. Costa de Carvalho ◽  
L.M. da Silva Oliveira ◽  
E. Futata Taniguchi ◽  
J.M. Zimbres ◽  
...  
Keyword(s):  
Immune Response ◽  
Lichen Planus ◽  
Innate Immune Response ◽  
Receptor Activation ◽  
Innate Immune ◽  
Toll Like Receptor

scholarly journals An α-Glucan ofPseudallescheria boydiiIs Involved in Fungal Phagocytosis and Toll-like Receptor Activation

2006 ◽  
Vol 281 (32) ◽  
pp. 22614-22623 ◽  
Author(s):  
Vera Carolina B. Bittencourt ◽  
Rodrigo T. Figueiredo ◽  
Rosana B. da Silva ◽  
Diego S. Mourão-Sá ◽  
Patricia L. Fernandez ◽  
...  
Keyword(s):  
Receptor Activation ◽  
Toll Like Receptor

scholarly journals Detection of Neu1 Sialidase Activity in Regulating TOLL-like Receptor Activation

10.3791/2142 ◽  
2010 ◽  
Author(s):  
Schammim R. Amith ◽  
Preethi Jayanth ◽  
Trisha Finlay ◽  
Susan Franchuk ◽  
Alanna Gilmour ◽  
...  
Keyword(s):  
Receptor Activation ◽  
Toll Like Receptor ◽  
Sialidase Activity ◽  
Neu1 Sialidase

scholarly journals Differential Requirement for TANK-binding Kinase-1 in Type I Interferon Responses to Toll-like Receptor Activation and Viral Infection

2004 ◽  
Vol 199 (12) ◽  
pp. 1651-1658 ◽  
Author(s):  
Andrea K. Perry ◽  
Edward K. Chow ◽  
Julia B. Goodnough ◽  
Wen-Chen Yeh ◽  
Genhong Cheng
Keyword(s):  
Viral Infection ◽  
Nuclear Translocation ◽  
Sendai Virus ◽  
Cell Types ◽  
Receptor Activation ◽  
Northern Blotting ◽  
Type I ◽  
Toll Like Receptor ◽  
Embryonic Fibroblasts ◽  
Iκb Kinase

TANK-binding kinase-1 (TBK1) and the inducible IκB kinase (IKK-i) have been shown recently to activate interferon (IFN) regulatory factor-3 (IRF3), the primary transcription factor regulating induction of type I IFNs. Here, we have compared the role and specificity of TBK1 in the type I IFN response to lipopolysaccharide (LPS), polyI:C, and viral challenge by examining IRF3 nuclear translocation, signal transducer and activator of transcription 1 phosphorylation, and induction of IFN-regulated genes. The LPS and polyI:C-induced IFN responses were abolished and delayed, respectively, in macrophages from mice with a targeted disruption of the TBK1 gene. When challenged with Sendai virus, the IFN response was normal in TBK1−/− macrophages, but defective in TBK1−/− embryonic fibroblasts. Although both TBK1 and IKK-i are expressed in macrophages, only TBK1 but not IKK-i was detected in embryonic fibroblasts by Northern blotting analysis. Furthermore, the IFN response in TBK1−/− embryonic fibroblasts can be restored by reconstitution with wild-type IKK-i but not a mutant IKK-i lacking kinase activity. Thus, our studies suggest that TBK1 plays an important role in the Toll-like receptor–mediated IFN response and is redundant with IKK-i in the response of certain cell types to viral infection.

scholarly journals NFκB1 is essential to prevent the development of multiorgan autoimmunity by limiting IL-6 production in follicular B cells

2016 ◽  
Vol 213 (4) ◽  
pp. 621-641 ◽  
Author(s):  
Elisha de Valle ◽  
George Grigoriadis ◽  
Lorraine A. O’Reilly ◽  
Simon N. Willis ◽  
Mhairi J. Maxwell ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Receptor Activation ◽  
Spontaneous Generation ◽  
B Cell Differentiation ◽  
Toll Like Receptor ◽  
Intrinsic Loss ◽  
And Function ◽  
Follicular B Cells

We examined the role of NFκB1 in the homeostasis and function of peripheral follicular (Fo) B cells. Aging mice lacking NFκB1 (Nfκb1−/−) develop lymphoproliferative and multiorgan autoimmune disease attributed in large part to the deregulated activity of Nfκb1−/− Fo B cells that produce excessive levels of the proinflammatory cytokine interleukin 6 (IL-6). Despite enhanced germinal center (GC) B cell differentiation, the formation of GC structures was severely disrupted in the Nfκb1−/− mice. Bone marrow chimeric mice revealed that the Fo B cell–intrinsic loss of NFκB1 led to the spontaneous generation of GC B cells. This was primarily the result of an increase in IL-6 levels, which promotes the differentiation of Fo helper CD4+ T cells and acts in an autocrine manner to reduce antigen receptor and toll-like receptor activation thresholds in a population of proliferating IgM+ Nfκb1−/− Fo B cells. We demonstrate that p50-NFκB1 represses Il-6 transcription in Fo B cells, with the loss of NFκB1 also resulting in the uncontrolled RELA-driven transcription of Il-6. Collectively, our findings identify a previously unrecognized role for NFκB1 in preventing multiorgan autoimmunity through its negative regulation of Il-6 gene expression in Fo B cells.

scholarly journals Endothelial Cells Are Main Producers of Interleukin 8 through Toll-Like Receptor 2 and 4 Signaling during Bacterial Infection in Leukopenic Cancer Patients

2003 ◽  
Vol 10 (4) ◽  
pp. 558-563 ◽  
Author(s):  
C. S. M. Oude Nijhuis ◽  
E. Vellenga ◽  
S. M. G. J. Daenen ◽  
W. A. Kamps ◽  
E. S. J. M. de Bont
Keyword(s):  
Endothelial Cells ◽  
Cancer Patients ◽  
Whole Blood ◽  
Neutralizing Antibodies ◽  
Bacterial Infections ◽  
Umbilical Vein ◽  
Interleukin 8 ◽  
Toll Like Receptor ◽  
Necrosis Factor Alpha ◽  
Umbilical Vein Endothelial Cells

ABSTRACT Cancer patients who are leukopenic due to chemotherapy are susceptible to bacterial infections. Normally, clinical conditions during bacterial infections are caused by pathogen-associated molecular patterns, which are components that bind to Toll-like receptor (TLR) 2 (TLR-2) and TLR-4 on leukocytes, resulting in the production of inflammatory cytokines. The mechanism of this inflammatory response in cancer patients with diminished numbers of leukocytes is not completely clear. The levels of interleukin 1β (IL-1β) and tumor necrosis factor alpha measured in the circulation of leukopenic cancer patients are lower than those measured in that of nonleukopenic patients during bacterial infections, whereas plasma interleukin 8 (IL-8) levels show distinct identical increases during bacterial infections in both leukopenic and nonleukopenic patients. Normally, these cytokines are mainly secreted by leukocytes. In cancer patients with bacterial infections and a diminished number of leukocytes, other sources of IL-8 production, such as endothelial cells, might be expected. Endothelial cells instead of leukocytes become the most important producers of IL-8 during bacterial infections in patients with chemotherapy-induced leukopenia through TLR-2 and TLR-4 signaling. Whole blood samples from six cancer patients were stimulated with lipopolysaccharide (LPS), and then IL-8 concentrations in supernatants were measured. Further, human umbilical vein endothelial cells (HUVECs) were incubated with sera from leukopenic cancer patients with or without bacterial infections, and then IL-8 concentrations in supernatants were measured (n = 6). In addition, the same HUVEC experiment was performed with the addition of neutralizing antibodies against TLR-2 and TLR-4. During leukopenia (<109 cells/liter), LPS stimulation of whole blood did not result in an increase in IL-8 levels. However, when endothelial cells were incubated with sera from leukopenic cancer patients during bacterial infections, a three- to eightfold increase in IL-8 production was found, compared to the IL-8 production found after incubation with sera from patients without signs of infections. This increase did not reflect a higher level of IL-8 already present in the sera. Further, we demonstrated that IL-8 production induced in endothelial cells by sera from patients with documented gram-negative infections could be reduced significantly by up to 40% when the cells were incubated with neutralizing antibodies against TLR-4 (P = 0.028). The addition of TLR-2 antibodies slightly enhanced the reduction of IL-8 production. These results suggest that during bacterial infections in cancer patients with markedly diminished numbers of leukocytes, endothelial cells become important producers of IL-8 through TLR-4 signaling and, to a lesser extent, TLR-2 signaling.

scholarly journals Interpretasi Hasil Pemeriksaan MRI Kardiak pada Penyakit Jantung Koroner

2013 ◽  
pp. 60-5
Author(s):  
Sony Hilal Wicaksono ◽  
Fachmi Ahmad Muslim ◽  
Vienna Rossimarina
Keyword(s):  
Computed Tomography ◽  
Ct Scan ◽  
Single Photon ◽  
Photon Emission ◽  
Emission Computed Tomography ◽  
Spect Mpi ◽  
Single Photon Emission Computed ◽  
Magnetic Resonance Imaging Mri ◽  
Photon Emission Computed Tomography ◽  
Tomography Scan

Seorang pasien dapat didiagnosis penyakit jantung koroner (PJK) melalui empat cara: kematian jantung mendadak, sindrom koroner akut, angina pektoris stabil paska revaskularisasi, dan hasil diagnostik noninvasif (Computed Tomography scan/CT scan koroner, Single Photon Emission Computed Tomography Myocardial Perfusion Imaging/SPECT MPI nuklir atau Magnetic Resonance Imaging/MRI)1. Pemeriksaan noninvasif memegang peranan penting, yaitu sebagai satu-satunya cara mendiagnosis PJK asimtomatik. Oleh sebab itu, pemahaman mengenai interpretasi hasil pemeriksaan noninvasif seperti CT scan koroner, SPECT MPI nuklir atau MRI kardiak dimasukkan dalam kompetensi dasar program pendidikan spesialis jantung dan pembuluh darah menurut Kolegium PERKI.

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