Serratia marcescens Serralysin Induces Inflammatory Responses through Protease-Activated Receptor 2

The Serratia marcescens-derived protease serralysin is consideredto play an important role in the pathogenesis of infection.Protease-activated receptor 2 (PAR-2) is activated by trypsin and alsoseveral other trypsin-like serine proteases, leading to the modulationof inflammatory and immune responses. However, little is known aboutthe activation of PAR-2 by bacterial proteases and its roles inbacterial infection. In this study, we investigated whether S.marcescens serralysin activates host inflammatory responsesthrough PAR-2. Our results demonstrated that serralysin inducesinterleukin-6 (IL-6) and IL-8 mRNA expression in a human lung squamouscell carcinoma, EBC-l cells. In addition, serralysin activatedactivator protein 1 (AP-1)-, CCAAT/enhancer-binding protein (C/EBP)-,and nuclear factor-κB (NF-κB)-driven promoters in EBC-1cells. An electrophoretic mobility shift assay showed that serralysinactivates the binding of AP-1, C/EBPβ, and NF-κB in thecells. Inactivation of serralysin resulted in the failure oftransactivation of AP-1-, C/EBP-, and NF-κB-driven promoters inthe cells. Furthermore, serralysin activated AP-1-, C/EBP-, andNF-κB-driven promoters via PAR-2 in HeLa cells. PAR-2antagonist peptides decreased serralysin-induced transactivation ofAP-1-, C/EBP-, and NF-κB-driven promoters in EBC-1 cells.Considered together, these results suggest that serralysin requiresPAR-2 to activate the critical transcription factors AP-1,C/EBPβ, and NF-κB for host inflammatoryresponses.