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Expression and Regulation of CCR1 by Airway Smooth Muscle Cells in Asthma¹

Philippe Joubert^*, Stéphane Lajoie-Kadoch^*, Mélanie Welman, Stephane Dragon, Séverine Létuvée^*, Barbara Tolloczko^*, Andrew J. Halayko, Abdelilah Soussi Gounni, Karim Maghni and Qutayba Hamid^2,*

^* Meakins-Christie Laboratories, McGill University, Montréal, Québec, Canada; Hôpital du Sacré-Coeur de Montréal, Research Center, Montréal, Québec, Canada; and University of Manitoba, Winnipeg, Manitoba, Canada

C-C chemokines such as CCL11, CCL5, and CCL3 are central mediators in the pathogenesis of asthma. They are mainly associated with the recruitment and the activation of specific inflammatory cells, such as eosinophils, lymphocytes, and neutrophils. It has recently been shown that they can also activate structural cells, such as airway smooth muscle and epithelial cells. The aims of this study were to examine the expression of the CCL3 receptor, CCR1, on human airway smooth muscle cells (ASMC) and to document the regulation of this receptor by cytokines involved in asthma pathogenesis. We first demonstrated that CCR1 mRNA is increased in the airways of asthmatic vs control subjects and showed for the first time that ASMC express CCR1 mRNA and protein, both in vitro and in vivo. Calcium mobilization by CCR1 ligands confirmed its functionality on ASMC. Stimulation of ASMC with TNF- and, to a lesser extent, IFN- resulted in an up-regulation of CCR1 expression, which was totally suppressed by both dexamethasone or mithramycin. Taken together, our data suggest that CCR1 might be involved in the pathogenesis of asthma, through the activation of ASMC by its ligands.

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 by Canadian Institutes for Health Research Grant MOP38011 and the Richard and Edith Strauss Canadian Foundation. Philippe Joubert is supported by a Canadian Institutes for Health Research/Canadian Lung Association/GlaxoSmithKline scholarship. Q.H. is a recipient of McGill University Health Center Strauss Chair in Respiratory Medicine. K.M. is a recipient of a scholarship from the Fonds de recherché en santé du Québec.

² Address correspondence and reprint requests Dr. Qutayba Hamid, Meakins-Christie Laboratories, 3626 St.-Urbain, Montréal, Québec, Canada H2X 2P2. E-mail address: qutayba.hamid{at}mcgill.ca

³ Abbreviations used in this paper: ASMC, airway smooth muscle cell; RT, room temperature; Sp1, stimulatory-protein-1; y.o., years old.

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