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J. Biol. Chem., Vol. 279, Issue 42, 44123-44132, October 15, 2004

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Induction of Genes Mediating Interferon-dependent Extracellular Trap Formation during Neutrophil Differentiation^*

Sibylla Martinelli, Mirjana Urosevic¶, Arezoo Daryadel, Patrick Antony Oberholzer¶, Christa Baumann||, Martin F. Fey||, Reinhard Dummer¶, Hans-Uwe Simon**, and Shida Yousefi

From the Department of Pharmacology, University of Bern, CH-3010 Bern, Switzerland, ^¶Department of Dermatology, University of Zurich, CH-8091 Zurich, Switzerland, and ^||Institute of Medical Oncology, Inselspital, University of Bern, CH-3010 Bern, Switzerland

Interferons (IFNs) are cytokines that possess potent anti-viral and immunoregulatory activities. In contrast, their potential role(s) in anti-bacterial defense and neutrophil activation mechanisms is less well explored. By comparing gene expression patterns between immature and mature human neutrophils, we obtained evidence that intracellular proteases and other anti-bacterial proteins are produced at earlier stages of maturation, whereas the genes for receptors and signaling molecules required for the release of these effector molecules are preferentially induced during terminal differentiation. For instance, mature neutrophils strongly expressed genes that increase their responses to type I and type II IFNs. Interestingly, granulocyte/macrophage colony-stimulating factor was identified as a repressor of IFN signaling components and consequently of IFN-responsive genes. Both IFN- and IFN- induced strong tyrosine phosphorylation of STAT1 in mature but not in immature neutrophils. Functional in vitro studies suggested that IFNs act as priming factors on mature neutrophils, allowing the formation of extracellular traps upon subsequent stimulation with complement factor 5a (C5a). In contrast, both IFN- and IFN- had only little capacity to prime immature cells in this system. Moreover, both IFNs did not have significant anti-proliferative effects on immature neutrophils. These data contribute to our understanding regarding changes of gene expression during neutrophil differentiation and IFN-mediated anti-bacterial defense mechanisms.

Received for publication, May 26, 2004 , and in revised form, July 16, 2004.

^* This work was supported by Swiss National Science Foundation Grants 31-68449.02 and 31-58916.99), the Bernische Krebsliga (Bern), and the Gottfried and Julia Bangerter-Rhyner Foundation (Zurich). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

^** To whom correspondence should be addressed: Dept. of Pharmacology, University of Bern, Friedbühlstrasse 49, CH-3010 Bern, Switzerland. Tel.: 41-31-632-3281; Fax: 41-31-632-4992; E-mail: hus{at}pki.unibe.ch.

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