CysLT1 Receptor Signaling Induces Transcriptional Upregulation of Proprotein Convertase Furin Expression: Potential Implications in Airway Remodeling

Upregulation of Proprotein Convertase Furin Expression: Potential Implications in Airway Remodeling M. Rola-Pleszczynski, C. Thompson, S. McMahon, Y. Bosse, C. M. Dubois, J. Stankova; Universite de Sherbrooke, Sherbrooke, PQ, CANADA. RATIONALE: Leukotriene (LT)D4 is suggested to play a role in airway remodeling, which is characterized by fibrogenesis and airway smooth muscle cell proliferation. In this study, we investigated the effects of LTD4 on the expression offurin, a proproteinconvertase involved in the maturation/activation of several substrates implicated in remodeling processes. METHODS: HEK293 cells stably transfected with the CysLT1 receptor were used to study the transcriptional regulation of furin expression by LTD4, using a co-transfected luciferase reporter gene upstream of the furin promoter. RT-PCR and Western blot analysis were used to measure mRNA and protein expression, respectively. RESULTS: Stimulation of the cells with LTD4 resulted in a timeand concentration-dependent induction of furin mRNA and protein expression. Selective transactivation of the P1 furin gene (fur) promoter was observed. A mutation in the AP-1 binding element of this promoter abrogated its transactivation by LTD4. Binding of AP-1 and GATA to the promoter following stimulation with LTD4 was confirmed by EMSA, and supershift assays indicated the formation of c-Jun/c-Fos and GATA4/6 complexes. LTD4 induced the maturation of the furin substrates MT1-MMP and TGFI1, with inhibition by the furin inhibitor I61-PDX. Finally, LTD4 induced furin gene expression in monocytic THP-1 cells which was abrogated using selective CysLT1 antagonists. CONCLUSIONS: 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. Funding: Canadian Institutes of Health Research