The uncovering of ESE-1 in human neutrophils: implication of its role in neutrophil function and survival

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Epithelium-specific Ets transcription factor 1 (ESE-1) is a member of the E26 transformation-specific family of transcription factors that has an epithelial-restricted constitutive expression but is induced by inflammatory stimuli in non-epithelial cells. Here we report that ESE-1 is constitutively expressed in human, but not in murine, neutrophils and that ESE-1 is modestly upregulated in septic patient neutrophils. In normal human neutrophils, ESE-1 was detected at both RNA and protein levels but was found to be an unstable nuclear protein ex vivo. ESE-1 transcription was also induced during all-trans retinoic acid-mediated HL-60 differentiation, a human promyelocytic cell line often used as an in vitro model of human neutrophils. Elf3−/− mice had normal neutrophils but a reduced number of circulating B-lymphocytes. These findings indicate a potential role of ESE-1 in regulating human neutrophil differentiation and function, and that it has different roles in the immune system of different species.

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  1. 1

    Maroulakou IG, Bowe DB . Expression and function of Ets transcription factors in mammalian development: a regulatory network. Oncogene 2000; 19: 6432–6442.

  2. 2

    Bartel FO, Higuchi T, Spyropoulos DD . Mouse models in the study of the Ets family of transcription factors. Oncogene 2000; 19: 6443–6454.

  3. 3

    Tymms MJ, Ng AY, Thomas RS, Schutte BC, Zhou J, Eyre HJ et al. A novel epithelial-expressed ETS gene, ELF3: human and murine cDNA sequences, murine genomic organization, human mapping to 1q32.2 and expression in tissues and cancer. Oncogene 1997; 15: 2449–2462.

  4. 4

    Oettgen P, Alani RM, Barcinski MA, Brown L, Akbarali Y, Boltax J et al. Isolation and characterization of a novel epithelium-specific transcription factor, ESE-1, a member of the ets family. Mol Cell Biol 1997; 17: 4419–4433.

  5. 5

    Oliver JR, Kushwah R, Hu J . Multiple roles of the epithelium-specific ETS transcription factor, ESE-1, in development and disease. Lab Invest 2011; 92: 320–330.

  6. 6

    Chang CH, Scott GK, Kuo WL, Xiong X, Suzdaltseva Y, Park JW et al. ESX: a structurally unique Ets overexpressed early during human breast tumorigenesis. Oncogene 1997; 14: 1617–1622.

  7. 7

    Kaplan MH, Wang XP, Xu HP, Dosik MH . Partially unspliced and fully spliced ELF3 mRNA, including a new Alu element in human breast cancer. Breast Cancer Res Treat 2004; 83: 171–187.

  8. 8

    He J, Pan Y, Hu J, Albarracin C, Wu Y, Dai JL . Profile of Ets gene expression in human breast carcinoma. Cancer Biol Ther 2007; 6: 76–82.

  9. 9

    Wu J, Duan R, Cao H, Field D, Newnham C, Koehler DR et al. Regulation of epithelium-specific Ets-like transcription factors ESE-1 and ESE-3 in airway epithelial cells. Cell Res 2008; 18: 649–663.

  10. 10

    Kushwah R, Oliver JR, Wu J, Chang Z, Hu J . Elf3 regulates allergic airway inflammation by controlling dendritic cell-driven T cell differentiation. J Immunol 2011; 187: 4639–4653.

  11. 11

    Bjerregaard MD, Jurlander J, Klausen P, Borregaard N, Cowland JB . The in vivo profile of transcription factors during neutrophil differentiation in human bone marrow. Blood 2003; 101: 4322–4332.

  12. 12

    Mantovani A, Cassatella MA, Costantini C, Jaillon S . Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol 2011; 11: 519–531.

  13. 13

    El Kebir D, Filep JG . Role of neutrophil apoptosis in the resolution of inflammation. ScientificWorldJournal 2010; 10: 1731–1748.

  14. 14

    Beyrau M, Bodkin JV, Nourshargh S . Neutrophil heterogeneity in health and disease: a revitalized avenue in inflammation and immunity. Open Biol 2012; 2: 120134.

  15. 15

    Grall F, Gu X, Tan L, Cho JY, Inan MS, Pettit AR et al. Responses to the proinflammatory cytokines interleukin-1 and tumor necrosis factor alpha in cells derived from rheumatoid synovium and other joint tissues involve nuclear factor kappaB-mediated induction of the Ets transcription factor ESE-1. Arthritis Rheum 2003; 48: 1249–1260.

  16. 16

    Zhan Y, Yuan L, Kondo M, Oettgen P . The counter-regulatory effects of ESE-1 during angiotensin II-mediated vascular inflammation and remodeling. Am J Hypertens 2010; 23: 1312–1317.

  17. 17

    Manavathi B, Rayala SK, Kumar R . Phosphorylation-dependent regulation of stability and transforming potential of ETS transcriptional factor ESE-1 by p21-activated kinase 1. J Biol Chem 2007; 282: 19820–19830.

  18. 18

    Breitman TR, Selonick SE, Collins SJ . Induction of differentiation of the human promyelocytic leukemia cell line (HL-60) by retinoic acid. Proc Natl Acad Sci USA 1980; 77: 2936–2940.

  19. 19

    Ozeki M, Shively JE . Differential cell fates induced by all-trans retinoic acid-treated HL-60 human leukemia cells. J Leukoc Biol 2008; 84: 769–779.

  20. 20

    Boxio R, Bossenmeyer-Pourie C, Steinckwich N, Dournon C, Nusse O . Mouse bone marrow contains large numbers of functionally competent neutrophils. J Leukoc Biol 2004; 75: 604–611.

  21. 21

    Slade E, Tamber PS, Vincent JL . The surviving sepsis campaign: raising awareness to reduce mortality. Crit Care 2003; 7: 1–2.

  22. 22

    Marshall JC . Why have clinical trials in sepsis failed? Trends Mol Med 2014; 20: 195–203.

  23. 23

    Raven K . Rodent models of sepsis found shockingly lacking. Nat Med 2012; 18: 998.

  24. 24

    Mestas J, Hughes CCW . Of mice and not men: differences between mouse and human immunology. J Immunol 2004; 172: 2731–2738.

  25. 25

    Hajjar E, Broemstrup T, Kantari C, Witko-Sarsat V, Reuter N . Structures of human proteinase 3 and neutrophil elastase—so similar yet so different. FEBS J 2010; 277: 2238–2254.

  26. 26

    Zollner O, Lenter MC, Blanks JE, Borges E, Steegmaier M, Zerwes HG et al. L-selectin from human, but not from mouse neutrophils binds directly to E-selectin. J Cell Biol 1997; 136: 707–716.

  27. 27

    Condliffe AM, Davidson K, Anderson KE, Ellson CD, Crabbe T, Okkenhaug K et al. Sequential activation of class IB and class IA PI3K is important for the primed respiratory burst of human but not murine neutrophils. Blood 2005; 106: 1432–1440.

  28. 28

    Gentile LF, Nacionales DC, Lopez MC, Vanzant E, Cuenca A, Cuenca AG et al. A better understanding of why murine models of trauma do not recapitulate the human syndrome. Crit Care Med 2014; 42: 1406–1413.

  29. 29

    Seok J, Warren HS, Cuenca AG, Mindrinos MN, Baker HV, Xu W et al. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci USA 2013; 110: 3507–3512.

  30. 30

    Morishima T, Watanabe K, Niwa A, Fujino H, Matsubara H, Adachi S et al. Neutrophil differentiation from human-induced pluripotent stem cells. J Cell Physiol 2011; 226: 1283–1291.

  31. 31

    Watson RWG, Rotstein OD, Parodo J, Bitar R, Marshall JC . The IL-1β-converting enzyme (Caspase-1) inhibits apoptosis of inflammatory neutrophils through activation of IL-1β. J Immunol 1998; 161: 957–962.

  32. 32

    Vancurova I, Miskolci V, Davidson D . NF-kappa B activation in tumor necrosis factor alpha-stimulated neutrophils is mediated by protein kinase Cdelta. Correlation to nuclear Ikappa Balpha. J Biol Chem 2001; 276: 19746–19752.

  33. 33

    Livak KJ, Schmittgen TD . Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 2001; 25: 402–408.

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We thank Arthur Gutierrez-Hartmann (University of Colorado) for his generous gift of the pEGFP-C3-empty and pEGFP-ESE-1 vectors. This study was funded by Canadian Institute for Health Research (CIHR) grant (MOP 125882) to Jim Hu. Chan Mi Lee is a recipient of Ontario Graduate Scholarship (OGS), Peterborough K.M. Hunter Studentship and SickKids Restracomp Studentship. We acknowledge that no authors have conflicting financial interests.

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Correspondence to J Hu.

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