Function of C/EBPδ in a regulatory circuit that discriminates between transient and persistent TLR4-induced signals

Litvak, Vladimir; Ramsey, Stephen A.; Rust, Alistair G.; Zak, Daniel E.; Kennedy, Kathleen A.; Lampano, Aaron E.; Nykter, Matti; Shmulevich, Ilya; Aderem, Alan

doi:10.1038/ni.1721

Cited by 252 publications

(333 citation statements)

References 37 publications

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“…C/EBPδ has been previously shown to be involved in the inflammatory response during persistent bacterial infection and has been suggested to act as an amplifier of the inflammatory response (7). Indeed, C/EBPδ −/− mice were able to resist a transient peritoneal infection with low-dose E. coli, but were highly susceptible to persistent peritoneal infection with high-dose E. coli.…”

Section: Discussionmentioning

confidence: 93%

CCAAT/enhancer-binding protein δ facilitates bacterial dissemination during pneumococcal pneumonia in a platelet-activating factor receptor-dependent manner

Duitman

Schouten

Groot

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The authors note that on page 13064, right column, first full paragraph, lines 4-7, "Some of the climatic events linked to such concerns are the severe droughts experienced by the Amazon basin in 2005 and 2010, which reportedly reduced tropical forest NPP by 1.6 to 2.2 PgC/y and increased tree mortality (50, 51)" should instead appear as "Some of the climatic events linked to such concerns are the severe droughts experienced by the Amazon basin in 2005 and 2010, which reportedly reduced tropical forest NPP and increased tree mortality by a total biomass carbon loss of 1.6 to 2.2 PgC (50, 51)."On page 13064, right column, first full paragraph, lines 12-17, "Assuming that the large reductions of tropical NPP reported previously (50, 51) are realistic, the absence of marked variations of the global CO 2 growth rate after the 2005 and 2010 Amazon droughts may imply that the drought conditions also coincidently reduced tropical Rh along with NPP, resulting in (relatively) small NEE anomalies" should instead appear as "Assuming that the large reductions of tropical forest biomass reported previously (50, 51) are realistic, the absence of marked variations of the global CO 2 growth rate after the 2005 and 2010 Amazon droughts may imply that the drought conditions also coincidently reduced tropical Rh along with NPP, resulting in (relatively) small NEE anomalies."These changes do not affect the conclusions of the article.

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Section: Discussionmentioning

confidence: 93%

CCAAT/enhancer-binding protein δ facilitates bacterial dissemination during pneumococcal pneumonia in a platelet-activating factor receptor-dependent manner

Duitman

Schouten

Groot

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Moreover, previous studies have shown that CEBP␦ was induced by proinflammatory signals, including TNF-␣ and IL-6, and that murine TLR4 stimulation leads to its activation in macrophages (23)(24)(25). We therefore determined whether activation of TLR8 signaling by R848 could lead to C/EBP␦ induction.…”

Section: R848 Enhances C/ebp␦ But Not C/ebp␤-mediated Induction Of Tlr8mentioning

confidence: 99%

C/EBPδ and STAT-1 Are Required for TLR8 Transcriptional Activity

Zannetti

Bonnay

Takeshita

et al. 2010

Journal of Biological Chemistry

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Toll-like receptor 8 (TLR8), which is expressed primarily in myeloid cells, plays a central role in initiating immune responses to viral single-stranded RNA. Despite the great interest in the field of TLR8 research, very little is known in terms of TLR8 biology and its transcriptional regulation. Here, we describe the isolation of the hTLR8 promoter and the characterization of the molecular mechanisms involved in its regulation. Reporter gene analysis and ChIP assays demonstrated that the hTLR8 regulation of the basal transcription is regulated via three C/EBP cis-acting elements that required C/EBP␦ and C/EBP␤ activity. In addition, we observed that R848 stimulation increases TLR8 transcriptional activity via an enhanced binding of C/EBP␦, and not C/EBP␤, to its responsive sites within the TLR8 promoter. Moreover, we showed that IFN-␥ also increased TLR8 transcription activity via the binding of STAT1 transcription factor to IFN-␥ activated sequence elements on the TLR8 promoter and enhanced TLR8 functionality. These results shed new light on the mechanisms involved during TLR8-mediated innate immune response.

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“…Not surprisingly, ATF3-deficient macrophages produce elevated levels of IL-6 and IL12p40 cytokines in response to TLR 4 activator, a bacterial LPS (13,15). Mechanistically, the negative regulation of transcription by ATF3 may occur indirectly via inhibition of C/EBPd, a positive regulator of cytokine gene induction (16). In addition, recent studies have shown that ATF3 mediates epigenetic regulation of proinflammatory cytokines (13,17).…”

mentioning

confidence: 99%

Novel Regulatory Action of Ribosomal Inactivation on Epithelial Nod2-Linked Proinflammatory Signals in Two Convergent ATF3-Associated Pathways

Park

Hun

Choi

et al. 2013

The Journal of Immunology

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In response to excessive nucleotide-binding oligomerization domain–containing protein 2 (Nod2) stimulation caused by mucosal bacterial components, gut epithelia need to activate regulatory machinery to maintain epithelial homeostasis. Activating transcription factor 3 (ATF3) is a representative regulator in the negative feedback loop that modulates TLR-associated inflammatory responses. In the current study, the regulatory effects of ribosomal stress-induced ATF3 on Nod2-stimulated proinflammatory signals were assessed. Ribosomal inactivation caused persistent ATF3 expression that in turn suppressed proinflammatory chemokine production facilitated by Nod2. Decreased chemokine production was due to attenuation of Nod2-activated NF-κB and early growth response protein 1 (EGR-1) signals by ATF3. However, the underlying molecular mechanisms involve two convergent regulatory pathways. Although ATF3 induced by ribosomal inactivation regulated Nod2-induced EGR-1 expression epigenetically through the recruitment of histone deacetylase 1, NF-κB regulation was associated with posttranscriptional regulation by ATF3 rather than epigenetic modification. ATF3 induced by ribosomal inactivation led to the destabilization of p65 mRNA caused by nuclear entrapment of transcript-stabilizing human Ag R protein via direct interaction with ATF3. These findings demonstrate that ribosomal stress-induced ATF3 is a critical regulator in the convergent pathways between EGR-1 and NF-κB, which contributes to the suppression of Nod2-activated proinflammatory gene expression.

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Function of C/EBPδ in a regulatory circuit that discriminates between transient and persistent TLR4-induced signals

Cited by 252 publications

References 37 publications

CCAAT/enhancer-binding protein δ facilitates bacterial dissemination during pneumococcal pneumonia in a platelet-activating factor receptor-dependent manner

CCAAT/enhancer-binding protein δ facilitates bacterial dissemination during pneumococcal pneumonia in a platelet-activating factor receptor-dependent manner

C/EBPδ and STAT-1 Are Required for TLR8 Transcriptional Activity

Novel Regulatory Action of Ribosomal Inactivation on Epithelial Nod2-Linked Proinflammatory Signals in Two Convergent ATF3-Associated Pathways

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