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Leukotriene D₄ Up-Regulates Furin Expression through CysLT1 Receptor Signaling

¹ Immunology Division, Department of Pediatrics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada

Correspondence and requests for reprints should be addressed to Marek Rola-Pleszczynski, MD, Immunology Division, Department of Pediatrics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001 North 12th Avenue, Sherbrooke, PQ, J1H 5N4 Canada. E-mail: marek.rola-pleszczynski{at}usherbrooke.ca

Leukotriene (LT)D₄ is suggested to play a role in airway remodeling, which is characterized by fibrogenesis and airway smooth muscle cell hyperplasia. In this study, we investigated the effects of LTD₄ on the expression of furin, a proprotein convertase involved in the maturation/activation of several substrates implicated in the remodeling processes. HEK293 cells stably transfected with the CysLT1 receptor were used to study the transcriptional regulation of furin by LTD₄. Stimulation of the cells with LTD₄ resulted in a time- and concentration-dependent induction of furin mRNA and protein expression. The study of furin gene (fur) promoters P1, P1A, and P1B revealed a selective transactivation of the P1 promoter by LTD₄. Mutations in the activator protein (AP)-1–binding element of the P1 promoter resulted in the partial loss of transactivation by LTD₄. Binding of AP-1 transcription factor to fur P1 promoter after stimulation with LTD₄ was demonstrated by electrophoretic mobility shift assay, and supershift assays indicated the formation of c-Jun/c-Fos complexes. LTD₄ induced the maturation of the furin substrates membrane-type 1 matrix metalloproteinase and transforming growth factor-β1, which was inhibited by the furin inhibitor 1-PDX. Finally, LTD₄ induced furin gene expression in monocytic THP-1 cells, which was abrogated using a selective CysLT1 receptor antagonist and inhibitors of the mitogen-activated protein kinases MEK-1, p38, and JunK. Our data show for the first time that LTD₄, via the CysLT1 receptor, can transcriptionally activate furin production with consequent maturation of furin substrates relevant to airway remodeling. These findings suggest that CysLT1 is involved in remodeling processes through modulation of furin transcription.

Key Words: cysteinyl-leukotriene • convertase • furin • activator protein-1 • membrane-type 1 matrix metalloproteinase