C/EBPβ serine 64, a phosphoacceptor site, has a critical role in LPS-induced IL-6 and MCP-1 transcription

Spooner, Chauncey J.; Sebastian, Thomas; Shuman, Jon D.; Durairaj, Srinivasan; Guo, Xiangrong; Johnson, Peter F.; Schwartz, Richard C.

doi:10.1016/j.cyto.2007.03.001

Cited by 10 publications

(9 citation statements)

References 57 publications

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“…Although this molecule can cause inflammation, inducing macrophages to secrete TNF-α and IL-6, thereby promoting insulin resistance, it also induces the production and activity of chemoattractant proteins such as monocyte chemotactic protein 1 (MCP-1), which promotes innate cellular immune responses and translocation in response to stimuli, such as HFD-induced adipose tissue hypertrophy and liver steatosis [39,40]. It is important to halt the production of inflammatory molecules, which are promoters of insulin resistance, so that macrophage infiltration is prevented, and any macrophages already infiltrating do not receive stimuli to remain infiltrated, as occurs with some drugs or with weight loss [41][42][43][44].…”

Section: Discussionmentioning

confidence: 99%

Modulation of gut microbiota by antibiotics improves insulin signalling in high-fat fed mice

et al. 2012

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Aims/hypothesis A high-fat dietary intake induces obesity and subclinical inflammation, which play important roles in insulin resistance. Recent studies have suggested that increased concentrations of circulating lipopolysaccharide (LPS), promoted by changes in intestinal permeability, may have a pivotal role in insulin resistance. Thus, we investigated the effect of gut microbiota modulation on insulin resistance and macrophage infiltration. Methods Swiss mice were submitted to a high-fat diet with antibiotics or pair-feeding for 8 weeks. Metagenome analyses were performed on DNA samples from mouse faeces. Blood was collected to determine levels of glucose, insulin, LPS, cytokines and acetate. Liver, muscle and adipose tissue proteins were analysed by western blotting. In addition, liver and adipose tissue were analysed, blinded, using histology and immunohistochemistry. Results Antibiotic treatment greatly modified the gut microbiota, reducing levels of Bacteroidetes and Firmicutes, overall bacterial count and circulating LPS levels. This modulation reduced levels of fasting glucose, insulin, TNF-α and IL-6; reduced activation of toll-like receptor 4 (TLR4), c-Jun N-terminal kinase (JNK), inhibitor of κ light polypeptide gene enhancer in B cells, kinase β (IKKβ) and phosphorylated IRS-1 Ser307; and consequently improved glucose tolerance and insulin tolerance and action in metabolically active tissues. In addition, there was an increase in portal levels of circulating acetate, which probably contributed to an increase in 5′-AMP-activated protein kinase (AMPK) phosphorylation in mice. We observed a striking reduction in crown-like structures (CLS) and F4/80 + macrophage cells in the adipose tissue of antibiotic-treated mice. Conclusions/interpretation These results suggest that modulation of gut microbiota in obesity can improve insulin signalling and glucose tolerance by reducing circulating LPS levels and inflammatory signalling. Modulation also appears to increase levels of circulating acetate, which activates AMPK and finally leads to reduced macrophage infiltration.

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Section: Discussionmentioning

confidence: 99%

Modulation of gut microbiota by antibiotics improves insulin signalling in high-fat fed mice

et al. 2012

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“…Further, in aortas from hyper-insulinaemic rats, C/EBPβ was shown to bind to MCP-1 DNA and induce the MCP-1 promoter, which may lead to initiate the process of atherosclerosis [37]. Finally, in a recent study, it was shown phosphorylation of serine 64 of C/EBPβ is necessary for C/EBPβ-activation of the MCP-1 promoter [38]. All these data corroborate with our data regarding the ability of C/EBPβ to activate the MCP-1 promoter.…”

Section: Discussionmentioning

confidence: 99%

St. John's Wort protein, p27SJ, regulates the MCP-1 promoter

Mukerjee

Deshmane

Darbinian

et al. 2008

Molecular Immunology

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St. John's Wort is commonly known for its antiviral, antidepressant, and cytotoxic properties, but traditionally St. John's Wort has also been used to treat inflammation. In this study, we sought to characterize the mechanisms used by St. John's Wort to treat inflammation by examining the effect of the recently isolated protein from St. John's Wort, p27 SJ on the expression of MCP-1. By employing an adenovirus expression vector, we demonstrate that a low concentration of p27 SJ upregulates the MCP-1 promoter through the transcription factor C/EBPβ. In addition, we found that C/EBPβ-homologous protein (CHOP) or siRNA-C/EBPβ significantly reduced the ability of p27 SJ to activate MCP-1 gene expression. Results from protein-protein interaction studies illustrate the existence of a physical interaction between p27 SJ and C/EBPβ in microglial cells. The use of chromatin immunoprecipitation assay (ChIP) led to the identification of a new cis-element that is responsive to C/EBPβ within the MCP-1 promoter. Association of C/EBPβ with MCP-1 DNA was not affected by the presence of p27 SJ . The biological activity of MCP-1 produced by cultures of adenovirus-p27 SJ transduced cells was increased relative to controls as measured by the transmigration of human Jurkat cells. Thus, we conclude that at high concentration, p27 SJ is a potential agent that may be developed as a modulator of MCP-1 leading to the inhibition of the cytokine-mediated inflammatory responses.

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“…7). Since changes in C/EBP-β phosphorylation states can affect C/EBP-β’s ability to transactivate target genes [38]; [63]; [64], we investigated recruitment to the SerpinB2 proximal promoter of the T 217 phosphorylated C/EBP-β isoform (p-C/EBP-β T217 ), which has been associated with cell survival [65]. p-C/EBP-β T217 was constitutively bound to the SerpinB2 proximal promoter and also present after 1 hr of LPS stimulation (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…C/EBP-β T188 is implicated in regulating DAPK1, an IFNγ-inducible gene involved in the regulation of cell cycle and apoptosis [38], processes with which SerpinB2 has also been associated [17]. C/EBP-β S64 is important for LPS-induced transcription of the cytokines IL-6 and MCP-1 [64]. Similarly, SerpinB2 is induced by LPS and regulated in a manner similar to cytokines [29].…”

Section: Resultsmentioning

confidence: 99%

The Transcription Factor C/EBP-β Mediates Constitutive and LPS-Inducible Transcription of Murine SerpinB2

et al. 2013

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SerpinB2 or plasminogen activator inhibitor type 2 (PAI-2) is highly induced in macrophages in response to inflammatory stimuli and is linked to the modulation of innate immunity, macrophage survival, and inhibition of plasminogen activators. Lipopolysaccharide (LPS), a potent bacterial endotoxin, can induce SerpinB2 expression via the toll-like receptor 4 (TLR4) by ∼1000-fold over a period of 24 hrs in murine macrophages. To map the LPS-regulated SerpinB2 promoter regions, we transfected reporter constructs driven by the ∼5 kb 5'-flanking region of the murine SerpinB2 gene and several deletion mutants into murine macrophages. In addition, we compared the DNA sequence of the murine 5′ flanking sequence with the sequence of the human gene for homologous functional regulatory elements and identified several regulatory cis-acting elements in the human SERPINB2 promoter conserved in the mouse. Mutation analyses revealed that a CCAAT enhancer binding (C/EBP) element, a cyclic AMP response element (CRE) and two activator protein 1 (AP-1) response elements in the murine SerpinB2 proximal promoter are essential for optimal LPS-inducibility. Electrophoretic mobility shift (EMSA) and chromatin immunoprecipitation (ChIP) assays demonstrated that LPS induces the formation of C/EBP-β containing complexes with the SerpinB2 promoter. Importantly, both constitutive and LPS-induced SerpinB2 expression was severely abrogated in C/EBP-β-null mouse embryonic fibroblasts (MEFs) and primary C/EBP-β-deficient peritoneal macrophages. Together, these data provide new insight into C/EBP-β-dependent regulation of inflammation-associated SerpinB2 expression.

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C/EBPβ serine 64, a phosphoacceptor site, has a critical role in LPS-induced IL-6 and MCP-1 transcription

Cited by 10 publications

References 57 publications

Modulation of gut microbiota by antibiotics improves insulin signalling in high-fat fed mice

Modulation of gut microbiota by antibiotics improves insulin signalling in high-fat fed mice

St. John's Wort protein, p27SJ, regulates the MCP-1 promoter

The Transcription Factor C/EBP-β Mediates Constitutive and LPS-Inducible Transcription of Murine SerpinB2

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