Role of CCAAT/Enhancer-Binding Protein Site in Transcription of Human Neutrophil Peptide-1 and -3 Defensin Genes

Tsutsumi‐Ishii, Yuko; Hasebe, Takeshi; Nagaoka, Isao

doi:10.4049/jimmunol.164.6.3264

Cited by 48 publications

(32 citation statements)

References 55 publications

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“…Earlier studies had reported that neither C/EBP␣ nor C/EBP␤ proteins are detectable in neutrophil nuclear extracts, be it in resting cells or following stimulation with TNF-␣ or LPS, and that, accordingly, no DNA binding to a C/EBP probe could be detected in EMSA (44,45). However, it should be noted that in these studies, nuclear extracts were prepared following cell disruption by detergent lysis in the absence of elastaseclass protease inhibitors, a procedure that results in the proteolysis of many neutrophil transcription factors (4).…”

Section: Discussionmentioning

confidence: 92%

Inflammatory Cytokine Production by Human Neutrophils Involves C/EBP Transcription Factors

Cloutier

Guindi

Larivée

et al. 2009

The Journal of Immunology

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A growing number of neutrophil-derived cytokines have proven to be crucial to various inflammatory and immune processes in vivo. Whereas C/EBP (CCAAT/enhancer-binding protein) transcription factors are important for neutrophil differentiation from myeloid precursors, we report herein that they also regulate cytokine production in mature neutrophils. All known C/EBP proteins but C/EBP␥ are expressed in neutrophils; most isoforms localize to the nucleus, except for C/EBP␣, which is cytoplasmic. Neutrophil stimulation does not alter the overall levels, cellular distribution, or turnover of C/EBP proteins; it also does not further induce the constitutive DNA-binding activity detected in nuclear extracts, consisting of C/EBP␤ and C/EBP. However, nuclear C/EBP␤ is rapidly phosphorylated upon cell stimulation, suggesting that it can activate cytokine promoters. Indeed, the transactivation of an IL-8 promoter-luciferase construct in a human neutrophil-like cell line was impaired when its C/EBP or NF-B sites were mutated. Overexpression of a C/EBP repressor also impeded IL-8 promoter transactivation, as well as the generation of IL-8, Mip-1␣, and Mip-1␤ in this cellular model, whereas TNF-␣ generation was mostly unaffected. Finally, overexpression of a C/EBP␤ mutant (T235A) as well as chromatin immunoprecipitation assays unveiled an important role for this residue in cytokine induction. This is the first demonstration that C/EBP factors are important regulators of cytokine expression in human neutrophils.

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Section: Discussionmentioning

confidence: 92%

Inflammatory Cytokine Production by Human Neutrophils Involves C/EBP Transcription Factors

Cloutier

Guindi

Larivée

et al. 2009

The Journal of Immunology

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“…42 Briefly, nuclear extracts were prepared from 1 ϫ 10 8 cells washed twice in ice-cold PBS, lysed in lysis buffer (10 mM HEPES-KOH, pH 7.9; 10 mM KCl; 0.2 mM EDTA; 1.5 mM MgCl 2 ; 0.5% NP-40; 1 mM DTT; 1 mM PMSF; protease inhibitors [complete mini, Roche Diagnostic]) on ice for 10 minutes, and washed once in the same buffer without NP-40.…”

Section: Gel Shift Assaymentioning

confidence: 99%

Up-regulation of MDR1 and induction of doxorubicin resistance by histone deacetylase inhibitor depsipeptide (FK228) and ATRA in acute promyelocytic leukemia cells

Tabe¹,

Konopleva

Contractor

et al. 2006

Blood

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The multidrug resistance 1 (MDR1) gene product P-glycoprotein (P-gp) is frequently implicated in cross-resistance of tumors to chemotherapeutic drugs. In contrast, acute promyelocytic leukemia (APL) cells do not express MDR1 and are highly sensitive to anthracyclines. The combination of ATRA and the novel histone deacetylase inhibitor (HDACI) depsipeptide (FK228) induced P-gp expression and prevented growth inhibition and apoptosis in NB4 APL cells subsequently exposed to doxorubicin (DOX). ATRA/ FK228 treatment after exposure to DOX, however, enhanced apoptosis. Both agents, ATRA or FK228, induced MDR1 mRNA. This effect was significantly enhanced by ATRA/FK228 administered in combination, due in part to increased H4 and H3-Lys9 acetylation of the MDR1 promoter and recruitment of the nuclear transcription factor Y alpha (NFYA) transcription activator to the CCAAT box. Cotreatment with specific P-gp inhibitor PSC833 reversed cytoprotective effects of ATRA/FK228. G 1 cell-cycle arrest and p21 mRNA induction were also observed in response to ATRA/FK228, which may IntroductionAcute promyelocytic leukemia (APL) cells are highly sensitive to anthracyclines in part due to the lack of expression of the multidrug resistance 1 (MDR1) protein P-glycoprotein (P-gp). 1,2 In this study, we investigated the effects of ATRA and FK228, alone and in combination, on the cytotoxicity of doxorubicin (DOX). Pretreatment by ATRA combined with FK228 prevented DOX-induced apoptosis in NB4 APL cells. However, when DOX treatment preceded ATRA/FK228, DOXinduced cell death was enhanced.The MDR1 gene product P-gp functions as a transmembrane efflux pump for a variety of chemotherapeutic drugs, including anthracyclines, [3][4][5][6] and overexpression of the MDR1 gene is a negative prognostic factor in acute myelogenous leukemias (AMLs). 7 Numerous studies have reported the successful inhibition of P-gp function in vitro using cyclosporine A, PSC833, and other compounds. [8][9][10][11] MDR1 gene expression can also be silenced, however, by epigenetic mechanisms involving histone deacetylases (HDACs) and DNA methyltransferases. [12][13][14][15][16] For example, the nuclear transcription factor Y (NF-Y) heteromeric complex binds to the CCAAT core sequence in the promoters of a variety of eukaryotic genes, including human MDR1, 12,[16][17][18] and acts as a histone acetylation regulator and transcription activator. 12,19 APL cells, which do not express MDR1, are associated with the oncogenic transcription factor PML-RAR␣ that represses transcription of the genes encoding the RA receptor targets through histone deacetylation. The PML-RAR␣ chimeric protein, moreover, has been suspected to be the factor suppressing MDR1 through chromatin remodeling. 20 A number of HDAC inhibitors (HDACIs) are currently being tested in clinical trials against a variety of cancers. Recently, there has been strong interest in HDACIs as anti-APL agents because of their synergistic activity with ATRA. [21][22][23][24] In vivo data demonstrated that HDACIs can overcome ...

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“…In mammals a number of cationic antibacterial peptides, such as defensins, are found in blood, secretions, epithelial tissues, and neutrophil granules (12)(13)(14)(15)(16). They are evolutionary ancient components that can kill the invading micro-organisms by perturbing their membranes and contribute to the innate host defense.…”

mentioning

confidence: 99%

Cathelicidin Family of Antibacterial Peptides CAP18 and CAP11 Inhibit the Expression of TNF-α by Blocking the Binding of LPS to CD14+ Cells

Nagaoka

Hirota

Niyonsaba

et al. 2001

The Journal of Immunology

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249

248

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Mammalian myeloid and epithelial cells express several kinds of antibacterial peptides (α-/β-defensins and cathelicidins) that contribute to the innate host defense by killing invading micro-organisms. In this study we evaluated the LPS-neutralizing activities of cathelicidin peptides human CAP18 (cationic antibacterial proteins of 18 kDa) and guinea pig CAP11 using the CD14+ murine macrophage cell line RAW264.7 and the murine endotoxin shock model. Flow cytometric analysis revealed that CAP18 and CAP11 inhibited the binding of FITC-conjugated LPS to RAW264.7 cells. Likewise, Northern and Western blot analyses indicated that CAP18 and CAP11 suppressed LPS-induced TNF-α mRNA and protein expression by RAW264.7 cells. Interestingly, CAP18 and CAP11 possessed LPS-binding activities, and they strongly suppressed the interaction of LPS with LPS binding protein that mediates the transport of LPS to CD14 to facilitate the activation of CD14+ cells by LPS. Moreover, when CAP18 and CAP11 were preincubated with RAW264.7 cells, they bound to the cell surface CD14 and inhibited the binding of FITC-LPS to the cells. Furthermore, in the murine endotoxin shock model, CAP18 or CAP11 administration inhibited the binding of LPS to CD14+ cells (peritoneal macrophages) and suppressed LPS-induced TNF-α expression by these cells. Together these observations indicate that cathelicidin peptides CAP18 and CAP11 probably exert protective actions against endotoxin shock by blocking the binding of LPS to CD14+ cells, thereby suppressing the production of cytokines by these cells via their potent binding activities for LPS and CD14.

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Role of CCAAT/Enhancer-Binding Protein Site in Transcription of Human Neutrophil Peptide-1 and -3 Defensin Genes

Cited by 48 publications

References 55 publications

Inflammatory Cytokine Production by Human Neutrophils Involves C/EBP Transcription Factors

Inflammatory Cytokine Production by Human Neutrophils Involves C/EBP Transcription Factors

Up-regulation of MDR1 and induction of doxorubicin resistance by histone deacetylase inhibitor depsipeptide (FK228) and ATRA in acute promyelocytic leukemia cells

Cathelicidin Family of Antibacterial Peptides CAP18 and CAP11 Inhibit the Expression of TNF-α by Blocking the Binding of LPS to CD14+ Cells

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