PU.1 and Interferon Consensus Sequence-binding Protein Regulate the Myeloid Expression of the Human Toll-like Receptor 4 Gene

Rehli, Michael; Poltorak, Alexander; Schwarzfischer, Lucia; Krause, Stefan W.; Andreesen, Reinhard; Beutler, Bruce

doi:10.1074/jbc.275.13.9773

Cited by 226 publications

(225 citation statements)

References 75 publications

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“…The levels of TLR4 mRNA expression in macrophages are regulated at the transcriptional as well as at a posttranscriptional level by altering its stability (25,41). Our data suggest that the effect of CRF peptides most probably occurs at the transcriptional level The Tlr4 gene is regulated at the transcriptional level through activation of transcription factors of the Ets family and primarily PU.1 (25), as well as AP-1 (26).…”

Section: Discussionmentioning

confidence: 76%

“…Our data suggest that the effect of CRF peptides most probably occurs at the transcriptional level The Tlr4 gene is regulated at the transcriptional level through activation of transcription factors of the Ets family and primarily PU.1 (25), as well as AP-1 (26). The minimal TLR4 promoter contains three PU.1-binding sites (28).…”

Section: Discussionmentioning

confidence: 99%

“…TLR4 is the principal mediator of macrophage response to LPS (24). TLR4 expression is primarily regulated by the transcription factor PU.1 (25). Recent experimental evidence indicate that AP-1 is also critical for TLR4 expression together with a distal-binding site of an Ets family protein and a GATA-like binding element (26).…”

mentioning

confidence: 99%

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Corticotropin-Releasing Factor and the Urocortins Induce the Expression of TLR4 in Macrophages via Activation of the Transcription Factors PU.1 and AP-1

Tsatsanis¹,

Androulidaki²,

Alissafi³

et al. 2006

The Journal of Immunology

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Corticotropin-releasing factor (CRF) augments LPS-induced proinflammatory cytokine production from macrophages. The aim of the present study was to determine the mechanism by which CRF and its related peptides urocortins (UCN) 1 and 2 affect LPS-induced cytokine production. We examined their role on TLR4 expression, the signal-transducing receptor of LPS. For this purpose, the murine macrophage cell line RAW 264.7 and primary murine peritoneal macrophages were used. Exposure of peritoneal macrophages and RAW 264.7 cells to CRF, UCN1, or UCN2 up-regulated TLR4 mRNA and protein levels. To study whether that effect occurred at the transcriptional level, RAW 264.7 cells were transfected with a construct containing the proximal region of the TLR4 promoter linked to the luciferase gene. CRF peptides induced activation of the TLR4 promoter, an effect abolished upon mutation of a proximal PU.1-binding consensus or upon mutation of an AP-1-binding element. Indeed, all three peptides promoted PU.1 binding to the proximal PU.1 site and increased DNA-binding activity to the AP-1 site. The effects of CRF peptides were inhibited by the CRF2 antagonist anti-sauvagine-30, but not by the CRF1 antagonist antalarmin, suggesting that CRF peptides mediated the up-regulation of TLR4 via the CRF2 receptor. Finally, CRF peptides blocked the inhibitory effect of LPS on TLR4 expression. In conclusion, our data suggest that CRF peptides play an important role on macrophage function. They augment the effect of LPS by inducing Tlr4 gene expression, through CRF2, via activation of the transcription factors PU.1 and AP-1.

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Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

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Corticotropin-Releasing Factor and the Urocortins Induce the Expression of TLR4 in Macrophages via Activation of the Transcription Factors PU.1 and AP-1

Tsatsanis¹,

Androulidaki²,

Alissafi³

et al. 2006

The Journal of Immunology

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“…54) clarified the species-specific variations of TLR expression in mice and humans. Recent data from several groups suggest that constitutive and inducible TLR expression in different cell types and in different species are controlled by transcriptional regulation (55)(56)(57). Moreover, gene regulatory elements found in the proximal promoters of TLR genes control cell-type specificity and inducible TLR expression in mice and humans.…”

Section: Discussionmentioning

confidence: 99%

The Toll-Like Receptor 5 Stimulus Bacterial Flagellin Induces Maturation and Chemokine Production in Human Dendritic Cells

Means

Hayashi

Smith

et al. 2003

The Journal of Immunology

357

273

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Toll-like receptors (TLRs) are pattern recognition receptors that serve an important function in detecting pathogens and initiating inflammatory responses. Upon encounter with foreign Ag, dendritic cells (DCs) go through a maturation process characterized by an increase in surface expression of MHC class II and costimulatory molecules, which leads to initiation of an effective immune response in naive T cells. The innate immune response to bacterial flagellin is mediated by TLR5, which is expressed on human DCs. Therefore, we sought to investigate whether flagellin could induce DC maturation. Immature DCs were cultured in the absence or presence of flagellin and monitored for expression of cell surface maturation markers. Stimulation with flagellin induced increased surface expression of CD83, CD80, CD86, MHC class II, and the lymph node-homing chemokine receptor CCR7. Flagellin stimulated the expression of chemokines active on neutrophils (IL-8/CXC chemokine ligand (CXCL)8, GRO-α/CXCL1, GRO-β/CXCL2, GRO-γ/CXCL3), monocytes (monocyte chemoattractant protein-1/CC chemokine ligand (CCL)2), and immature DCs (macrophage-inflammatory protein-1α/CCL3, macrophage-inflammatory protein-1β/CCL4), but not chemokines active on effector T cells (IFN-inducible protein-10 kDa/CXCL10, monokine induced by IFN-γ/CXCL9, IFN-inducible T cell α chemoattractant/CXCL11). However, stimulating DCs with both flagellin and IFN-inducible protein-10 kDa, monokine induced by IFN-γ, and IFN-inducible T cell α chemoattractant expression, whereas stimulation with IFN-β or flagellin alone failed to induce these chemokines. In functional assays, flagellin-matured DCs displayed enhanced T cell stimulatory activity with a concomitant decrease in endocytic activity. Finally, DCs isolated from mouse spleens or bone marrows were shown to not express TLR5 and were not responsive to flagellin stimulation. These results demonstrate that flagellin can directly stimulate human but not murine DC maturation, providing an additional mechanism by which motile bacteria can initiate an acquired immune response.

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“…Analysis of the human TLR4 promoter has identified a functional interaction between the PU.1 and interferon consensus sequence binding protein (ICSBP) transcription factors that regulates the basal expression of this TLR family member in myeloid cells. 24 The minimal promoter for human TLR2 has also been defined and contains binding sites for several transcription factors including Sp1 and Ets family members. 25 Notably, the human and murine TLR2 promoters lack sequence homology and exhibit differential activation in response to several PAMPs including LPS and mycoplasma macrophage activating lipopeptide 2 kD (MALP 2).…”

Section: Mammalian Tlrsmentioning

confidence: 99%

Toll-like receptors and their role in experimental models of microbial infection

2003

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Effective host defense against microbial infection depends upon prompt recognition of pathogens, activation of immediate containment measures, and ultimately the generation of a specific and definitive adaptive immune response. The innate immune system of the host is responsible for providing constant surveillance against infection; when confronted by pathogens it deploys a series of rapidly acting antimicrobial effectors while simultaneously instructing the adaptive immune system as to the nature and context of the infectious threat. Pathogen recognition and activation of innate immunity is mediated by members of the Toll-like receptor (TLR) family through detection of conserved microbial structures that are absent from the host. Experimental models of infection using TLR-deficient mice, as well as limited human studies, have clearly demonstrated the critical role of TLRs in host defense against most major groups of mammalian pathogens.

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PU.1 and Interferon Consensus Sequence-binding Protein Regulate the Myeloid Expression of the Human Toll-like Receptor 4 Gene

Cited by 226 publications

References 75 publications

Corticotropin-Releasing Factor and the Urocortins Induce the Expression of TLR4 in Macrophages via Activation of the Transcription Factors PU.1 and AP-1

Corticotropin-Releasing Factor and the Urocortins Induce the Expression of TLR4 in Macrophages via Activation of the Transcription Factors PU.1 and AP-1

The Toll-Like Receptor 5 Stimulus Bacterial Flagellin Induces Maturation and Chemokine Production in Human Dendritic Cells

Toll-like receptors and their role in experimental models of microbial infection

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