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Eosinophil-Derived Cationic Proteins Activate the Synthesis of Remodeling Factors by Airway Epithelial Cells¹

Sophie Pégorier^*, Lori A. Wagner, Gerald J. Gleich^, and Marina Pretolani^2,*

^* Institut National de la Santé et de la Recherche Médicale, Unité 700, Université Paris 7, Faculté de Médecine Denis Diderot, Site Xavier Bichat, Paris, France; and Department of Dermatology and Department of Medicine, University of Utah, Salt Lake City, UT 84132

Eosinophil cationic proteins influence several biological functions of the respiratory epithelium, yet their direct contribution to airway remodeling has not been established. We show that incubation of the human bronchial epithelial cell line, BEAS-2B, or primary cultured human bronchial epithelial cells, normal human bronchial epithelial cells, with subcytotoxic concentrations (0.1, 0.3, and 1 µM) of major basic protein (MBP), or eosinophil peroxidase (EPO), augmented the transcripts of endothelin-1, TGF-, TGF-1, platelet-derived growth factor (PDGF)-, epidermal growth factor receptor, metalloproteinase (MMP)-9, fibronectin, and tenascin. A down-regulation of MMP-1 gene expression was observed exclusively in BEAS-2B cells. Cationic protein-induced transcriptional effects were followed by the release of endothelin-1, PDGF-AB in the supernatants by ELISA, and by a down- and up-regulation, respectively, in the levels of MMP-1 and MMP-9 in cell lysates, by Western blot. Cell stimulation with the synthetic polycation, poly-L-arginine, reproduced some but not all effects of MBP and EPO. Finally, simultaneous cell incubation with the polyanion molecules, poly-L-glutamic acid or heparin, restored MMP-1 gene expression but incompletely inhibited MBP- and EPO-induced transcriptional effects as well as endothelin-1 and PDGF-AB release, suggesting that cationic proteins act partially through their cationic charge. We conclude that eosinophil-derived cationic proteins are able to stimulate bronchial epithelium to synthesize factors that influence the number and behavior of structural cells and modify extracellular matrix composition and turnover.

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.

¹ This work was supported in part by the "Agence Nationale de la Recherche" (Grant Number 0012405), by the Chancellerie des Universités de Paris en Sorbonne (fellowship to S.P.), Paris, France, and by the U.S. National Institutes of Health (Grant AI09728).

² Address correspondence and reprint requests to Dr. Marina Pretolani, Institut National de la Santé et de la Recherche Médicale, Unité 700, Université Paris 7, Faculté de Médecine Denis Diderot, Site Xavier Bichat, 16 rue Henri Huchard, 75018 Paris, France. E-mail address: mpretol{at}bichat.inserm.fr

³ Abbreviations used in this paper: ECM, extracellular matrix; MMP, metalloproteinase; MBP, major basic protein; EPO, eosinophil peroxidase; NHBE, normal human bronchial epithelial cell; LDH, lactate dehydrogenase; C_t, cycle threshold; EGF, epidermal growth factor; PDGF, platelet-derived growth factor; ET-1, endothelin-1.

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