Histone deacetylase inhibitors decrease Toll‐like receptor‐mediated activation of proinflammatory gene expression by impairing transcription factor recruitment

Bode, Konrad A.; Schroder, Kate; Hume, David; Ravasi, Timothy; Heeg, Klaus; Sweet, Matthew J.; Dalpke, Alexander H.

doi:10.1111/j.1365-2567.2007.02678.x

Cited by 159 publications

(164 citation statements)

References 51 publications

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“…Thereby usually gene expression is shut down. In contrast, the production of the interleukin 12 subunit p40 in DCs after TLR stimulation was found to be positively regulated by HDACs, probably by facilitating recruitment of transcription factors (157).…”

Section: Tlrs In Rheumatoid Arthritis (Ra)mentioning

confidence: 89%

TLRs and chronic inflammation

Ospelt

Gay

2010

The International Journal of Biochemistry & Cell Biology

162

127

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After the discovery of Toll-like receptors (TLRs), innate immune mechanisms came back in the focus of scientific research. With more and more mechanisms of TLR biology known, it has become clear that these and also other innate immune receptors are not only of crucial importance in the immune response to invading pathogens, but also play a role in the homeostasis of commensal flora and in the response to stress and danger signals. In this respect, increasing evidence is found that inappropriate quantity or quality of TLR ligands or aberrant response to TLR activation plays a role in a variety of chronic inflammatory diseases. In this review, an overview of the currently known TLRs and their signaling pathways is given and reports about their expression and activation in chronic inflammatory diseases are recapitulated. TLRs and chronic inflammation Abstract:After the discovery of Toll-like receptors (TLRs), innate immune mechanisms came back in the focus of scientific research. With more and more mechanisms of TLR biology known, it has become clear that these and also other innate immune receptors are not only of crucial importance in the immune response to invading pathogens, but also play a role in the homeostasis of commensal flora and in the response to stress and danger signals. In this respect, increasing evidence is found that inappropriate quantity or quality of TLR ligands or aberrant response to TLR activation plays a role in a variety of chronic inflammatory diseases.In this review, an overview of the currently known TLRs and their signaling pathways isgiven and reports about their expression and activation in chronic inflammatory diseases are recapitulated.2

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Section: Tlrs In Rheumatoid Arthritis (Ra)mentioning

confidence: 89%

TLRs and chronic inflammation

Ospelt

Gay

2010

The International Journal of Biochemistry & Cell Biology

162

127

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“…The ChIP assay was carried out as described by Natoli and coworkers [50] modified by Bode et al [51]. One-twentieth of the immunoprecipitated DNA was used in quantitative PCR.…”

Section: Chipmentioning

confidence: 99%

PD‐L1 expression on tolerogenic APCs is controlled by STAT‐3

et al. 2011

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During infection, TLR agonists are released and trigger mature as well as differentiating innate immune cells. Early encounter with TLR agonists (R848; LPS) blocks conventional differentiation of CD14 1 monocytes into immature dendritic cells (iDCs) resulting in a deviated phenotype. We and others characterized these APCs (TLR-APC) by a retained expression of CD14 and a lack of CD1a. Here, we show in addition, expression of programmed death ligand-1 (PD-L1). TLR-APCs failed to induce T-cell proliferation and furthermore were able to induce CD25 1 Foxp3 1 T regulatory cells (Tregs). Since PD-L1 is described as a key negative regulator and inducer of tolerance, we further analyzed its regulation. PD-L1 expression was regulated in a MAPK/cytokine/STAT-3-dependent manner: high levels of IL-6 and IL-10 that signal via STAT-3 were produced by TLR-APCs. Blocking of STAT-3 activation prevented PD-L1 expression. Moreover, chromatin immunoprecipitation revealed direct binding of STAT-3 to the PD-L1 promoter. Those findings indicate a pivotal role of STAT-3 in regulating PD-L1 expression. MAPKs were indirectly engaged, as blocking of p38 and p44/42 MAPKs decreased IL-6 and IL-10 thus reducing STAT-3 activation and subsequent PD-L1 expression. Hence, during DC differentiation TLR agonists induce a STAT-3-mediated expression of PD-L1 and favor the development of tolerogenic APCs.Keywords: DC . PD-L1 . STAT-3 . Tolerance . TLR See accompanying Commentary by Sumpter and ThomsonSupporting Information available online IntroductionDC are initiators and modulators of the adaptive immune response [1]. They are able to induce T-cell activation as well as T-cell tolerance. During infection, DCs are confronted with pathogen-associated molecular patterns (PAMP), which in turn trigger effector functions in innate immune cells. For example, immature DCs (iDCs) generated from monocytes by in vitro culture with GM-CSF and IL-4 (G4) mature and become fully activated upon stimulation with TLR agonists. Mature DCs (mDCs) in turn activate most efficiently naïve T cells [2]. However, during infection induction of inhibitory immune pathways can also be observed [3,4]. Here, we investigate an alternative TLR-induced APC phenotype, which inhibits immune reactivity. It has been shown that encounter of monocytes with LPS during the very beginning of the differentiation process blocks conventional differentiation to iDCs. A phenotypically distinct APC type (TLR-APC) is generated, characterized by a [5][6][7]. Activation of p38 MAPK, the secretion of IL-10 and the inactivation of ERK and NF-kB [7] have been correlated with the generation of TLR-APCs. LPS-treated cells showed in addition an intense STAT-3 phosphorylation. Differentiation processes of DCs are plastic and can be influenced by various factors, e.g. cytokines. Many cytokines mediate their cellular response via the JAK/STAT signaling pathway thereby controlling the status of transcription and cellular differentiation. For instance, during the maturation of DCs, a switch occurs from constit...

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“…For pre-mRNA RT-PCR, total RNA was isolated and reverse transcribed as above. RT-PCR assays were performed as previously described (18).…”

Section: Quantitative Rt-pcrmentioning

confidence: 99%

Kinetic of RelA Activation Controls Magnitude of TLR-Mediated IL-12p40 Induction

Bode

Schmitz

Vargas

et al. 2009

The Journal of Immunology

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IL-12 is a crucial cytokine for dendritic cell-mediated induction of Th 1 cell differentiation. TLR ligands induce IL-12 to differing extents. Stimulation of dendritic cells allowed for the differentiation of three groups of TLRs; potency to induce IL-12 decreased in the order of TLR7/9, TLR3/4, and TLR1/2/6 stimulation. The MAPK, PI3K, and IRF (IFN regulatory factor) signaling pathways could be ruled out to be the cause for the differences in IL-12p40 induction. However, we observed that stimulation of dendritic cells with different TLR ligands resulted in striking differences in the kinetics of NF-κB activation. LPS induced a rapid but short-lived activation of RelA, whereas CpG-DNA stimulation resulted in prolonged RelA activity at the IL-12p40 promoter. Only TLR2 and TLR4 ligands were capable of inducing S536 phosphorylation of RelA, which has been proposed to be responsible for early termination of NF-κB activation. It is suggested that differences in the kinetics of a common TLR signaling module affect the biological response patterns of various TLRs, with IL-12p40 being a gene that needs prolonged NF-κB activation.

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Histone deacetylase inhibitors decrease Toll‐like receptor‐mediated activation of proinflammatory gene expression by impairing transcription factor recruitment

Cited by 159 publications

References 51 publications

TLRs and chronic inflammation

TLRs and chronic inflammation

PD‐L1 expression on tolerogenic APCs is controlled by STAT‐3

Kinetic of RelA Activation Controls Magnitude of TLR-Mediated IL-12p40 Induction

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