C/EBP regulates the promoter of the eosinophil-derived neurotoxin/RNS2 gene in human eosinophilic cells

Baltus, Belinda; Buitenhuis, Miranda; Dijk, Thamar B. van; Vinson, Charles; Raaijmakers, J. A. M.; Lammers, Jan-Willem; Koenderman, Leo; Groot, Rolf P. de

doi:10.1002/jlb.66.4.683

Cited by 16 publications

(20 citation statements)

References 48 publications

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“…Thus, two of the human C/EBP⑀ isoforms have the capacity to act as negative regulators of myeloid gene expression. Of interest, the lack of transactivating activity by any of the C/EBP⑀ isoforms for the MBP-P2 promoter is in agreement with the essential inactivity of the C/EBP⑀ 32 isoform relative to other C/EBP family members for another eosinophil secondary granule protein gene, the eosinophil-derived neurotoxin (EDN, RNS2) promoter (105).…”

Section: Discussionsupporting

confidence: 63%

Novel Combinatorial Interactions of GATA-1, PU.1, and C/EBPε Isoforms Regulate Transcription of the Gene Encoding Eosinophil Granule Major Basic Protein

Stankiewicz

Yang

et al. 2002

Journal of Biological Chemistry

106

139

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GATA-1 and the ets factor PU.1 have been reported to functionally antagonize one another in the regulation of erythroid versus myeloid gene transcription and development. The CCAAT enhancer binding protein ⑀ (C/EBP⑀) is expressed as multiple isoforms and has been shown to be essential to myeloid (granulocyte) terminal differentiation. We have defined a novel synergistic, as opposed to antagonistic, combinatorial interaction between GATA-1 and PU.1, and a unique repressor role for certain C/EBP⑀ isoforms in the transcriptional regulation of a model eosinophil granulocyte gene, the major basic protein (MBP). The eosinophil-specific P2 promoter of the MBP gene contains GATA-1, C/EBP, and PU.1 consensus sites that bind these factors in nuclear extracts of the eosinophil myelocyte cell line, AML14.3D10. The promoter is transactivated by GATA-1 alone but is synergistically transactivated by low levels of PU.1 in the context of optimal levels of GATA-1. The C/EBP⑀ 27 isoform strongly represses GATA-1 activity and completely blocks GATA-1/PU.1 synergy. In vitro mutational analyses of the MBP-P2 promoter showed that both the GATA-1/PU.1 synergy, and repressor activity of C/EBP⑀ 27 are mediated via protein-protein interactions through the C/EBP and/or GATA-binding sites but not the PU.1 sites. Co-immunoprecipitations using lysates of AML14.3D10 eosinophils show that both C/EBP⑀ 32/30 and ⑀ 27 physically interact in vivo with PU.1 and GATA-1, demonstrating functional interactions among these factors in eosinophil progenitors. Our findings identify novel combinatorial protein-protein interactions for GATA-1, PU

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Section: Discussionsupporting

confidence: 63%

Novel Combinatorial Interactions of GATA-1, PU.1, and C/EBPε Isoforms Regulate Transcription of the Gene Encoding Eosinophil Granule Major Basic Protein

Stankiewicz

Yang

et al. 2002

Journal of Biological Chemistry

106

139

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“…While it is unclear why EDN would have a special function in TPE, there are studies suggesting that eosinophilic granular proteins are under differential regulatory control, most notably following treatment for filarial infection (10). EDN has also been shown to have its own promoter, which is regulated by the transcriptional factor C/EBP, indicating that there may be differential transcriptional regulation of the eosinophil granule proteins (ECPs) (5). Although it is not surprising that EDN, an eosinophilic granular protein, is elevated in this disease characterized by hypereosinophilia, it is perplexing that EDN, but not ECP, was increased in the lungs and blood of TPE patients in our study.…”

Section: Discussionmentioning

confidence: 99%

Localized Eosinophil Degranulation Mediates Disease in Tropical Pulmonary Eosinophilia

et al. 2003

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To explore the mechanisms underlying the eosinophil-mediated inflammation of tropical pulmonary eosinophilia (TPE), bronchoalveolar lavage (BAL) fluid, serum, and supernatants from pulmonary and blood leukocytes (WBC) from patients with acute TPE (n ‫؍‬ 6) were compared with those obtained from healthy uninfected individuals (n ‫؍‬ 4) and from patients with asthma (n ‫؍‬ 4) or elephantiasis (n ‫؍‬ 5). Although there were no significant differences in the levels of interleukin-4 (IL-4), IL-5, IL-13, eotaxin, granulocyte-macrophage colony-stimulating factor, RANTES, or eosinophil cationic protein, there was a marked increase in eosinophil-derived neurotoxin (EDN) both systemically and in the lungs of individuals with TPE compared to each of the control groups (P < 0.02). Moreover, there was a compartmentalization of this response, with EDN levels being higher in the BAL fluid than in the serum (P < 0.02). Supernatants from WBC from either whole blood or BAL cells were examined for chemokines, cytokines, eosinophil degranulation products, and arachidonic acid metabolites. Of the many mediators examined-particularly those associated with eosinophil trafficking-only EDN (in BAL fluid and WBC) and MIP-1␣ (in WBC) levels were higher for TPE patients than for the non-TPE control groups (P < 0.02). These data suggest it is the eosinophilic granular protein EDN, an RNase capable of damaging the lung epithelium, that plays the most important role in the pathogenesis of TPE.Tropical pulmonary eosinophilia (TPE), an unusual manifestation of human lymphatic filarial infection, is characterized by an eosinophilic pulmonary inflammatory infiltrate and marked elevations of immunoglobulin E (IgE) and circulating eosinophils in the serum, all felt to be mediated by immunologic hyperreactivity to filarial parasites or their antigens. Although 129 million people worldwide are infected with lymphatic filariasis, Ͻ0.01% develop TPE (20). It is unclear what factors predispose patients to the rare, localized, and profound immune dysregulation associated with TPE.

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“…In subsequent studies, de Groot and co-workers (22,23) demonstrated that both PU.1 and C/EBP consensus sites were crucial for EDN expression, and recently Wang et al (24) identified regulatory elements in a 34-bp proximal promoter segment shared among primate EDNs. In this study, we focus on the extended 1000-bp 5Ј promoter of EDN and utilize RNA silencing methods to explore the specific roles of GATA-1 and GATA-2 transcription factors in promoting its expression.…”

mentioning

confidence: 99%

GATA Transcription Factors Regulate the Expression of the Human Eosinophil-derived Neurotoxin (RNase 2) Gene

Qiu

Dyer

Rådinger

et al. 2009

Journal of Biological Chemistry

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The transcription factors GATA-1 and GATA-2 have been implicated in promoting differentiation of eosinophilic leukocytes. In this study, we examined the roles of GATA-1 and GATA-2 in activating transcription of the secretory ribonuclease, the eosinophil-derived neurotoxin (EDN/RNase 2). Augmented expression of both GATA-1 and GATA-2 was detected in eosinophil promyelocyte HL-60 clone 15 cells in response to biochemical differentiation with butyric acid. Deletion or mutation of one or both of the two consensus GATA-binding sites in the extended 1000-bp 5 promoter of the EDN gene resulted in profound reduction in reporter gene activity. Antibody-augmented electrophoretic mobility shift and chromatin immunoprecipitation analyses indicate that GATA-1 and GATA-2 proteins bind to both functional GATA consensus sequences in the EDN promoter. Interestingly, RNA silencing of GATA-1 alone had no impact on EDN expression; silencing of GATA-2 resulted in diminished expression of EDN, and also diminished expression of GATA-1 in both butyric acid-induced HL-60 clone 15 cells and in differentiating human eosinophils derived from CD34 ؉ hematopoietic progenitors. Likewise, overexpression of GATA-2 in uninduced HL-60 clone 15 cells resulted in augmented transcription of both EDN and GATA-1. Taken together, our data suggest that GATA-2 functions directly via interactions with the EDN promoter and also indirectly, via its ability to regulate the expression of GATA-1 in differentiating eosinophils and eosinophil cell lines.

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C/EBP regulates the promoter of the eosinophil-derived neurotoxin/RNS2 gene in human eosinophilic cells

Cited by 16 publications

References 48 publications

Novel Combinatorial Interactions of GATA-1, PU.1, and C/EBPε Isoforms Regulate Transcription of the Gene Encoding Eosinophil Granule Major Basic Protein

Novel Combinatorial Interactions of GATA-1, PU.1, and C/EBPε Isoforms Regulate Transcription of the Gene Encoding Eosinophil Granule Major Basic Protein

Localized Eosinophil Degranulation Mediates Disease in Tropical Pulmonary Eosinophilia

GATA Transcription Factors Regulate the Expression of the Human Eosinophil-derived Neurotoxin (RNase 2) Gene

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