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 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 following stimulation with LTD₄ was demonstrated by EMSA, and supershift assays indicated the formation of c-Jun/c-Fos complexes. LTD₄ induced the maturation of the furin substrates MT1-MMP and TGF1, 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 MAP 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 the implication of CysLT1 in remodeling processes through modulation of furin transcription.