Microbial Products Stimulate Human Toll-like Receptor 2 Expression through Histone Modification Surrounding a Proximal NF-κB-binding Site

Johnson, Christopher M.; Tapping, Richard I.

doi:10.1074/jbc.m705151200

Cited by 42 publications

(37 citation statements)

References 43 publications

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“…In human monocytes and murine macrophages, TLR2 up-regulation is mediated by chromatin remodeling (80) and histone acetylation (79), respectively, whereas in epithelial cells p38MAP kinase acts as a negative regulator of TLR2 up-regulation (81). In contrast to epithelial cells, our results and those of An et al (82) indicate that p38MAP kinase is partly responsible for the TLR2 up-regulation observed on stimulated TDC.…”

Section: Discussioncontrasting

confidence: 56%

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TLR Triggering on Tolerogenic Dendritic Cells Results in TLR2 Up-Regulation and a Reduced Proinflammatory Immune Program

Chamorro

García-Vallejo

Unger

et al. 2009

The Journal of Immunology

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Tolerogenic dendritic cells (TDC) offer a promising therapeutic potential to ameliorate autoimmune diseases. Reported to inhibit adaptive immune responses, little is known about their innate immunity receptor repertoire. In this study, we compared three types of human TDC (IL-10-DC, dexamethasone (DX)-DC, and 1,25(OH)2D3-DC) by their TLR expression and response to a set of TLR ligands. TDC are endowed with the same TLR set as standard monocyte-derived dendritic cells but respond differentially to the TLR stimuli Pam3CSK4, polyinosinic-polycytidylic acid, LPS, and flagellin. TDC expressed low or no IL-12-related cytokines and remarkably elevated IL-10 levels. Interestingly, only TDC up-regulated the expression of TLR2 upon stimulation. This boosted the tolerogenic potential of these cells, because IL-10 production was up-regulated in TLR2-stimulated, LPS-primed DX-DC, whereas IL-12 and TNF-α secretion remained low. When comparing the TDC subsets, DX-DC and 1,25(OH)2D3-DC up-regulated TLR2 irrespective of the TLR triggered, whereas in IL-10-DC this effect was only mediated by LPS. Likewise, DX-DC and 1,25(OH)2D3-DC exhibited impaired ability to mature, reduced allostimulatory properties, and hampered capacity to induce Th1 differentiation. Therefore, both DX-DC and 1,25(OH)2D3-DC display the strongest tolerogenic and anti-inflammatory features and might be most suitable tools for the treatment of autoimmune diseases.

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Section: Discussioncontrasting

confidence: 56%

“…The regulation of TLR2 expression has been only partly elucidated (50,79,80). In human monocytes and murine macrophages, TLR2 up-regulation is mediated by chromatin remodeling (80) and histone acetylation (79), respectively, whereas in epithelial cells p38MAP kinase acts as a negative regulator of TLR2 up-regulation (81).…”

Section: Discussionmentioning

confidence: 99%

TLR Triggering on Tolerogenic Dendritic Cells Results in TLR2 Up-Regulation and a Reduced Proinflammatory Immune Program

Chamorro

García-Vallejo

Unger

et al. 2009

The Journal of Immunology

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“…Simpson (23); pXJ40 (transcription enhancer factor (TEF))-1 and pXJ40-related (R)TEF-1 (containing human TEF-1 and RTEF-1 cDNA, respectively) were from A. F. R. Stewart (24); p65 expression vector was from R. I. Tapping (25); p53 wild type, p53…”

Section: Methodsmentioning

confidence: 99%

Expression of S100A6 in Cardiac Myocytes Limits Apoptosis Induced by Tumor Necrosis Factor-α

Tsoporis

Izhar

Parker

2008

Journal of Biological Chemistry

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S100A6 is induced in myocardium post-infarction in vivo and in response to growth factors and inflammatory cytokines in vitro. Forced expression of S100A6 in cardiomyocytes inhibits regulation of cardiac specific gene expression in response to trophic stimulation. To define regulation and function of S100A6, we characterized the human S100A6 promoter and mapped upstream regulatory elements in rat neonatal cardiac myocytes, fibroblasts, and vascular smooth muscle cells and defined a functional role for S100A6 in tumor necrosis factor-␣-induced myocyte apoptosis. The functional S100A6 promoter was localized to region ؊167/؉134 containing 167 upstream base pairs. The S100A6 promoter is regulated by positive (؊361/ ؊167 and ؊588/؊361) and negative (؊1371/؊1194) elements. Tumor necrosis factor-␣ induced the maximal S100A6 promoter and transcription factor NF-B (p65 subunit). Electrophoretic mobility shift showed that tumor necrosis factor-␣ induced p65 binding to a potential NF-B-binding site at ؊460/ ؊451. Chromatin immunoprecipitation analysis revealed p65 is recruited to the S100A6 promoter upon tumor necrosis factor-␣ stimulation. The NF-B inhibitor caffeic acid phenethyl ester and mutation of the NF-B-binding site inhibited S100A6 promoter activation by tumor necrosis factor-␣. Tumor necrosis factor-␣ induced cardiac myocyte apoptosis. Specific inhibition of S100A6 using a small interfering RNA directed against S100A6 potentiated tumor necrosis factor-␣-induced myocyte apoptosis, whereas overexpression of S100A6 by gene transfer prevented tumor necrosis factor-␣-induced myocyte apoptosis by interfering with p53 phosphorylation. These results demonstrate that S100A6 is induced by tumor necrosis factor-␣ via an NF-B-dependent mechanism, serving a role in homeostasis to limit tumor necrosis factor-␣-induced apoptosis by regulating p53 phosphorylation.

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“…Surprisingly, TLR2 and TLR4 were not detected on the surface of eosinophils from normal donors, in contrast to eosinophils from eosinophilic donors, which spontaneously expressed surface TLR2 and TLR4 (Figure 2A). Because TLR expression is known to be up-regulated in human monocytes treated with TLR agonists, 28 we investigated whether BCG could also modulate surface expression of TLRs on eosinophils. For 16 healthy donors and eosinophilic donors studied (Table S1), BCG significantly increased TLR2 and TLR4 expression on freshly isolated human eosinophils from most donors (Figure 2A,B).…”

Section: Eosinophil Expression Of Tlr2 and Tlr4 Is Induciblementioning

confidence: 99%

TLR2-dependent eosinophil interactions with mycobacteria: role of α-defensins

Driss

Legrand

Hermann

et al. 2009

Blood

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Peripheral blood and tissue eosinophilia are a prominent feature in allergic diseases and during helminth infections. Eosinophil recruitment also frequently occurs upon mycobacterial infections, particularly in lung granuloma. However, the mechanism by which eosinophils interact with mycobacteria remains largely unknown. Because eosinophils recently have been shown to be involved in innate immune responses, we investigated the direct interactions of eosinophils with Mycobacterium bovis BCG as a study model. We show that live BCG attracts human eosinophils and induces reactive oxygen species (ROS) synthesis, granule protein release, and tumor necrosis factor (TNF)-␣ secretion. Using anti-TLR2 neutralizing antibodies before exposure of eosinophils to BCG, we showed a critical role of TLR2 signaling in ROS and eosinophil peroxidase release. BCG-induced eosinophil activation is mediated through the p38 mitogen-activated protein (MAP) kinase and nuclear factor (NF)-B pathways. In addition, a mycobacterial wall component, lipomannan, induced a TLR2-dependent eosinophil activation. In addition, we showed that eosinophils express and produce ␣-defensins upon stimulation with BCG and lipomannan and that ␣-defensins could inhibit mycobacterial growth in synergy with eosinophil cationic protein. These results suggest a role for human eosinophils as direct effectors in TLR2-mediated innate immunity against mycobacteria and confer to these cells potent cytotoxic functions through defensin and eosinophil cationic protein production. (Blood. 2009;113:3235-3244) IntroductionTuberculosis is the most prevalent infectious disease worldwide, accounting for 3 million deaths annually. Control of Mycobacterium tuberculosis bacillus (MTB) infection requires the development of a Th1-type CD4 T-cell response and activation of alveolar macrophages, leading to the formation of lung granuloma. 1 Initial recognition of mycobacteria by the innate immune system through pathogen recognition receptors (PRRs) such as Toll-like receptors (TLRs) contributes to triggering this adaptive immune response. 2 Indeed, cooperation between TLR2, TLR4, and TLR9 may contribute to resistance against mycobacteria, 3 and the authors of several studies have shown that mycobacterial components act as TLR agonists. Indeed, lipomannans (LM) and lipoarabinomannans (LAM), lipoglycans that ubiquitously are found in the wall of mycobacteria, are involved in the release of proinflammatory or anti-inflammatory cytokines. 4 Whereas mycobacterial infections are rather associated to Th1 responses, the occurrence of Th2 cytokine responses also has been reported in human tuberculosis. It is suggested that these Th2 responses might depress macrophage immunity and lead to increased susceptibility to tuberculosis. 5 Th2-driven immunity is associated with cell types that seldom are studied during mycobacterial infections. Among them, eosinophils, which are now considered as multifunctional leukocytes, are involved in inflammatory processes as well as in modulation of innate and ad...

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Microbial Products Stimulate Human Toll-like Receptor 2 Expression through Histone Modification Surrounding a Proximal NF-κB-binding Site

Cited by 42 publications

References 43 publications

TLR Triggering on Tolerogenic Dendritic Cells Results in TLR2 Up-Regulation and a Reduced Proinflammatory Immune Program

TLR Triggering on Tolerogenic Dendritic Cells Results in TLR2 Up-Regulation and a Reduced Proinflammatory Immune Program

Expression of S100A6 in Cardiac Myocytes Limits Apoptosis Induced by Tumor Necrosis Factor-α

TLR2-dependent eosinophil interactions with mycobacteria: role of α-defensins

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