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J. Biol. Chem., Vol. 283, Issue 44, 29983-29992, October 31, 2008

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Cell-specific Regulation of PTX3 by Glucocorticoid Hormones in Hematopoietic and Nonhematopoietic Cells^*

Andrea Doni^{12 3}, Giovanna Mantovani¹, Chiara Porta, Jan Tuckermann^¶, Holger M. Reichardt^||, Anna Kleiman^¶, Marina Sironi, Luca Rubino, Fabio Pasqualini, Manuela Nebuloni^**, Stefano Signorini, Giuseppe Peri, Antonio Sica, Paolo Beck-Peccoz, Barbara Bottazzi, and Alberto Mantovani²³

From the Istituto Clinico Humanitas, Istituto Di Ricerca Cura a Caratte Re Scientifico (IRCCS), Department of Immunology and Inflammation, Rozzano, Milan, Italy, the Department of Medical Sciences, Endocrine Unit, University of Milan, Fondazione Policlinico, IRCCS, Milan, Italy, ^¶Molecular Biology of Tissue-specific Hormone Action, Leibniz Institute for Age Research Fritz-Lipmann, Jena, Germany, the ^||Department of Cellular and Molecular Immunology, University of Goettingen, Humboldtallee, Goettingen, Germany, the Department of Laboratory Medicine, Hospital of Desio, Desio, Milan, Italy, the ^**Pathology Unit, Luigi Sacco Department of Clinical Sciences, University of Milan, Milan, Italy, and the Institute of General Pathology, University of Milan, Milan, Italy

PTX3 (prototypic long pentraxin 3) is a fluid phase pattern recognition receptor, which plays nonredundant roles in the resistance against diverse pathogens, in the assembly of a hyaluronic acid-rich extracellular matrix, and in female fertility. Inflammatory signals induce production of PTX3 in diverse cell types, including myeloid dendritic cells (DC), fibroblasts, and endothelial cells (EC). The present study was designed to explore the effect of glucocorticoid hormones (GC) on PTX3 production in different cellular contexts. In myeloid DC, GC inhibited the PTX3 production. In contrast, in fibroblasts and EC, GC alone induced and, under inflammatory conditions, enhanced and extended PTX3 production. In vivo administration of GC augmented the blood levels of PTX3 in mice and humans. Moreover, patients with Cushing syndrome had increased levels of circulating PTX3, whereas PTX3 levels were decreased in subjects affected by iatrogenic hypocortisolism. In nonhematopoietic cells, GC receptor (GR) functioned as a ligand-dependent transcription factor (dimerization-dependent) to induce PTX3 gene expression. In contrast, in hematopoietic cells, GR repressed PTX3 gene transcription by interfering (dimerization-independent) with the action of other signaling pathways, probably NFB and AP-1. Thus, divergent effects of GC were found to be due to different GR mechanisms. The results presented here indicate that GC have divergent effects on PTX3 production in hematopoietic (DC and macrophages) and nonhematopoietic (fibroblasts and EC) cells. The divergent effects of GC on PTX3 production probably reflect the different functions of this multifunctional molecule in innate immunity and in the construction of the extracellular matrix.

Received for publication, July 23, 2008

^* This work was supported by Associazione Italiana per la Ricerca sul Cancro; Ministero Istruzione, Università e Ricerca; and European Commission Mugen Grant 005203, Muvapred Grant 503240, and DC-Thera Grant 512074. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S5.

¹ Both of these authors contributed equally to the work.

² To whom correspondence may be addressed. E-mail: andrea.doni{at}humanitas.it. ³ To whom correspondence may be addressed: Istituto Clinico Humanitas (ICH), via Manzoni, 56 20089 Rozzano, Milan, Italy. Tel.: 39-0282242445; Fax: 39-0282245101; E-mail: alberto.mantovani{at}humanitas.it.

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