The Response of Secondary Genes to Lipopolysaccharides in Macrophages Depends on Histone Deacetylase and Phosphorylation of C/EBPβ

Serrat, Neus; Sebastián, Carlos; Pereira-Lopes, Selma; Valverde‐Estrella, Lorena; Lloberas, Jorge

doi:10.4049/jimmunol.1203500

Cited by 32 publications

(22 citation statements)

References 55 publications

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“…This ranking parallels the effectiveness of the anti-inflammatory activity of SCFAs395960. Propionate failed to inhibit TNF but not IL-6 and IL-12p40 induced by LPS in BMDMs, which mirrored previous observations obtained with trichostatin A and suberanilohydroxamic acid2944616263. Propionate strongly increased H3 and H4 acetylation in BMDMs which, like BMDCs, barely expressed Ffar2 and Ffar3 41.…”

Section: Discussionsupporting

confidence: 87%

Impact of the microbial derived short chain fatty acid propionate on host susceptibility to bacterial and fungal infections in vivo

Ciarlo

Heinonen

Herderscheê

et al. 2016

Sci Rep

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Short chain fatty acids (SCFAs) produced by intestinal microbes mediate anti-inflammatory effects, but whether they impact on antimicrobial host defenses remains largely unknown. This is of particular concern in light of the attractiveness of developing SCFA-mediated therapies and considering that SCFAs work as inhibitors of histone deacetylases which are known to interfere with host defenses. Here we show that propionate, one of the main SCFAs, dampens the response of innate immune cells to microbial stimulation, inhibiting cytokine and NO production by mouse or human monocytes/macrophages, splenocytes, whole blood and, less efficiently, dendritic cells. In proof of concept studies, propionate neither improved nor worsened morbidity and mortality parameters in models of endotoxemia and infections induced by gram-negative bacteria (Escherichia coli, Klebsiella pneumoniae), gram-positive bacteria (Staphylococcus aureus, Streptococcus pneumoniae) and Candida albicans. Moreover, propionate did not impair the efficacy of passive immunization and natural immunization. Therefore, propionate has no significant impact on host susceptibility to infections and the establishment of protective anti-bacterial responses. These data support the safety of propionate-based therapies, either via direct supplementation or via the diet/microbiota, to treat non-infectious inflammation-related disorders, without increasing the risk of infection.

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Section: Discussionsupporting

confidence: 87%

Impact of the microbial derived short chain fatty acid propionate on host susceptibility to bacterial and fungal infections in vivo

Ciarlo

Heinonen

Herderscheê

et al. 2016

Sci Rep

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“…Though a potential binding sequence of Mef2C was found at approximately 2Kb upstream from the transcription starting site of C/EBPβ, there is no documented evidence showing functional binding of Mef2C to this region, and further investigations are needed to determine its function. Regulation of C/EBPβ at translational as well as post-translational levels has also been reported (42 – 44), so post-transcriptional regulation of C/EBPβ by Mef2C cannot be excluded.…”

Section: Discussionmentioning

confidence: 99%

1,25-Dihydroxyvitamin D3 induces monocytic differentiation of human myeloid leukemia cells by regulating C/EBPβ expression through MEF2C

Zheng

Wang

Studzinski

2015

The Journal of Steroid Biochemistry and Molecular Biology

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Myogenic enhancer factor2 (Mef2) consists of a family of transcription factors involved in morphogenesis of skeletal, cardiac and smooth muscle cells. Among the four isoforms (Mef2A, 2B, 2C, and 2D), Mef2C was also found to play important roles in hematopoiesis. At myeloid progenitor level, Mef2C expression favors monocytic differentiation. Previous studies from our laboratory demonstrated that ERK5 was activated in 1,25-dihydroxyvitamin D3 (1,25D)-induced monocytic differentiation in AML cells and ERK5 activation was accompanied by increased Mef2C phosphorylation. We therefore examined the role of Mef2C in 1,25D-induced monocytic differentiation in AML cell lines (HL60, U937 and THP1) and found that knockdown of Mef2C with small interfering RNA (siRNA) significantly decreases the expression of the monocytic marker, CD14, without affecting the expression of the general myeloid marker, CD11b. CCAAT/Enhancer-binding protein (C/EBP) β, which can bind to CD14 promoter and increase its transcription, has been shown to be the downstream effector of 1,25D-induced monocytic differentiation in AML cells. When Mef2C was knocked down, expression of C/EBPβ was reduced at both mRNA and protein levels. The protein expression levels of cell cycle regulators, p27Kip1 and cyclin D1, were not affected by Mef2C knockdown, nor the monopoiesis related transcription factor, ATF2 (Activating Transcription Factor 2). Thus, we conclude that 1,25D-induced monocytic differentiation, and CD14 expression in particular, is mediated through activation of ERK5-Mef2C-C/EBPβ signaling pathway, and that Mef2C does not seem to modulate cell cycle progression.

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“…22 HDAC-7 could promote TLR4-dependent proinflammatory gene expression in macrophages. 15 Accordingly, HDAC inhibitor TSA could specifically inhibit LPSdependent gene expression in inflammatory macrophages 23 or epithelial cells. 24 TSA was also reported to suppress cell proliferation and epithelial-mesenchymal transition through inactivation of the component of LPS/TLR4 signaling pathway, such as phosphatidylinositol-3-kinase (PI3K)/Akt, p38 mitogen-activated protein kinase (MAPK), and extracellular signal-regulated kinase(ERK)1/2 pathways.…”

Section: Discussionmentioning

confidence: 99%

HDAC is essential for epigenetic regulation of Thy-1 gene expression during LPS/TLR4-mediated proliferation of lung fibroblasts

Xing

Nie

et al. 2015

Laboratory Investigation

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Lipopolysaccharide (LPS)-induced proliferation of lung fibroblasts is closely correlated with loss of gene expression of thymocyte differentiation antigen-1 (Thy-1), accompanied with deacetylation of histones H3 and H4 at the Thy-1 gene promoter region; however, the mechanism remains enigmatic. We report here that LPS downregulates Thy-1 gene expression by activating histone deacetylases (HDACs) via Toll-like receptor 4 (TLR4) signaling. Treatment of primary cultured mouse lung fibroblasts with LPS resulted in significant upregulation of TLR4 and enhanced cell proliferation that was abolished by silencing TLR4 with lentivirus-delivered TLR4 shRNA. Interestingly, LPS increased the mRNA and protein levels of HDAC-4, -5, and -7, an effect that was abrogated by HDAC inhibitor trichostatin A (TSA) or TLR4-shRNA-lentivirus. Consistent with these findings, Ace-H3 and Ace-H4 were decreased by LPS that was prevented by TSA. Most importantly, chromosome immunoprecipitation (ChIP) analysis demonstrated that LPS decreased the association of Ace-H4 at the Thy-1 promoter region that was efficiently restored by pretreatment with TSA. Accordingly, LPS decreased the mRNA and protein levels of Thy-1 that was inhibited by TSA. Furthermore, silencing the Thy-1 gene by lentivirus-delivered Thy-1 shRNA could promote lung fibroblast proliferation, even in the absence of LPS. Conversely, overexpressing Thy-1 gene could inhibit lung fibroblast proliferation and reduce LPS-induced lung fibroblast proliferation. Our data suggest that LPS upregulates and activates HDACs through TLR4, resulting in deacetylation of histones H3 and H4 at the Thy-1 gene promoter that may contribute to Thy-1 gene silencing and lung fibroblast proliferation. Pulmonary fibrosis is characterized by aberrant proliferation and activation of lung fibroblasts. 1,2 The phenotypic transition of lung fibroblasts during the process of pulmonary fibrosis can be stimulated by various pathological conditions, including lipopolysaccharide (LPS), a component of bacteria membranes and an important player during the development of pulmonary fibrosis. 3,4 LPS-induced proliferation of lung fibroblast is associated with the silencing of thymocyte differentiation antigen-1 (Thy-1) and deacetylation of histones H3 and H4 at the Thy-1 gene promoter; 5,6 however, the mechanism by which LPS promotes the deacetylation of histones H3 and H4 leading to downregulation of Thy-1 gene expression is largely unknown.Thy-1 is a cell surface glycoprotein that is present in normal lung fibroblasts but absent from the fibroblastic foci of idiopathic pulmonary fibrosis (IPF). 7 Heterogeneous surface expression of Thy-1 in fibroblasts results in the specialization of fibroblast, including Thy-1 (+) and Thy-1 (− ) subsets. Hagood et al 5,8,9 reported that lack of Thy-1 expression on lung fibroblasts contributed to IPF. Recently, it was found that epigenetic mechanisms, such as promoter hypermethylation and histone modification, play an important role in Thy-1 gene silencing in lung fibroblasts. 6,7 Our...

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The Response of Secondary Genes to Lipopolysaccharides in Macrophages Depends on Histone Deacetylase and Phosphorylation of C/EBPβ

Cited by 32 publications

References 55 publications

Impact of the microbial derived short chain fatty acid propionate on host susceptibility to bacterial and fungal infections in vivo

Impact of the microbial derived short chain fatty acid propionate on host susceptibility to bacterial and fungal infections in vivo

1,25-Dihydroxyvitamin D3 induces monocytic differentiation of human myeloid leukemia cells by regulating C/EBPβ expression through MEF2C

HDAC is essential for epigenetic regulation of Thy-1 gene expression during LPS/TLR4-mediated proliferation of lung fibroblasts

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